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Microbiome and Anticancer Immunosurveillance
Abstract
Anticancer immune responses can be considered a desirable form of autoimmunity that may be profoundly shaped by the microbiome. Here, we discuss evidence for the microbiome's influence on anti-tumor immunosurveillance, including those that are indirect and can act at a distance, and we put forward hypotheses regarding mechanisms of how these effects are implemented. These may involve cross-reactivity between microbial and tumor antigens shaping T cell repertoires and/or microbial products stimulating pattern recognition receptors that influence the type and intensity of immune responses. Understanding how the microbiome impacts natural cancer immunosurveillance as well as treatment-induced immune responses will pave the way for more effective therapies and prophylactics.
... Despite the clinical approval of several ICIs for cancer treatment, challenges persist, including low response rates and the emergence of drug resistance in many cases (6,(39)(40)(41)(42)(43). The intricate interplay between intestinal microorganisms and host immunity can indirectly influence cancer patients' responses to ICIs ( Figure 1) (44,45). For instance, active Enterococcus secreted antigen A (Sag A), may enhance host immunity by interacting with nucleotide-binding oligomerization domain 2 (NOD2), potentially augmenting the anti-tumor effects of anti-PD-L1 therapy (46). ...
... For instance, active Enterococcus secreted antigen A (Sag A), may enhance host immunity by interacting with nucleotide-binding oligomerization domain 2 (NOD2), potentially augmenting the anti-tumor effects of anti-PD-L1 therapy (46). In the realm of anti-tumor immunity, microbial communities exert regulatory control over metabolites through the stimulation of pathogen-related molecular patterns, thereby contributing to the formation of an adaptive immune repertoire by inducing cross-reactive T cell responses (44,(47)(48)(49). ...
... Zitvogel et al. proposed two hypotheses to elucidate the microbial mechanisms underlying tumor immune surveillance (44). Alongside the non-antigen pathway, which involves microorganisms modulating T cell anti-tumor activity through metabolites derived from pathogen-associated molecular patterns (PAMPs), an antigen pathway exists (69). ...
Immunotherapy has revolutionized cancer treatment by leveraging the immune system’s innate capabilities to combat malignancies. Despite the promise of tumor antigens in stimulating anti-tumor immune responses, their clinical utility is hampered by limitations in eliciting robust and durable immune reactions, exacerbated by tumor heterogeneity and immune evasion mechanisms. Recent insights into the immunogenic properties of host homologous microbial antigens have sparked interest in their potential for augmenting anti-tumor immunity while minimizing off-target effects. This review explores the therapeutic potential of microbial antigen peptides in tumor immunotherapy, beginning with an overview of tumor antigens and their challenges in clinical translation. We further explore the intricate relationship between microorganisms and tumor development, elucidating the concept of molecular mimicry and its implications for immune recognition of tumor-associated antigens. Finally, we discuss methodologies for identifying and characterizing microbial antigen peptides, highlighting their immunogenicity and prospects for therapeutic application.
... Since then, thousands of genes and their respective antibody-recognized tumor antigen peptides have been determined using SEREX methods [8,9]. Over the past 30 years, researchers have identified large numbers of genes and tumor antigens recognized by the mechanisms of specific immunity [7][8][9][10][11][12][13][14][15][16][17]. Those determinations have enabled us to better understand the nature of tumor-associated antigens (TAAs) recognized by the cellular and humoral immune system. ...
... Those determinations have enabled us to better understand the nature of tumor-associated antigens (TAAs) recognized by the cellular and humoral immune system. The human immune system, particularly the leukocytes, patrols tissues to eliminate invading pathogens, dying/dead cells, and senescent cells [14]. These mechanisms include recognizing and destroying malignant cells that expresses TAAs. ...
... Sivan et al. emphasized that enthusiasm has been fueled by recent clinical success, particularly with antibodies that block immune inhibitory pathways, specifically CTLA-4 and the axis between PD-1 and its ligand 1 (PD-L1) [13]. This prompted Zitvogel et al. to hypothesize that c-BIF might have antigens sufficiently similar to human tumor antigens to be capable of eliciting tumor-specific T lymphocytes and antibodies recognizing future tumor cells via antigenic mimicry [14] (Figure 1). Vétizou et al. revealed that T cells that are specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade [20]. ...
In this comprehensive review, we explore the pivotal role of commensal Bifidobacterium (c-BIF) as potent non-self-antigens through antigenic mimicry, along with exploring the potential of humoral immune responses for both malignant and non-malignant disease. c-BIF, a predominant component of the human gut microbiome encompassing around 90% of the human genome, has emerged as a pivotal player in human biology. Over recent decades, there has been extensive research elucidating the intricate connections between c-BIF and various facets of human health, with particular emphasis on their groundbreaking impact on anti-cancer effects and the management of non-malignant diseases. The multifaceted role of c-BIF is explored, ranging from enhancing anti-tumor immunity to improving the efficacy of anti-cancer and anti-infectious disease strategies, and serving as predictive biomarkers for various diseases. Recent studies highlight not only c-BIF’s promotion of anti-tumor immunity but also their role in enhancing the efficacy of immune checkpoint inhibitors. The review emphasizes the promising avenue of manipulating the gut microbiota, particularly c-BIF, for modulating cancer immunotherapy with targeted effects on tumor cells while minimizing harm to normal tissue. In the context of infectious and inflammatory diseases, the crucial role of c-BIFs in the management of COVID-19 symptoms is examined, emphasizing their impact on the severity of and immune response to COVID-19. Furthermore, c-BIF exhibits preventive and therapeutic effects on Human Papillomaviruses (HPV) and shows promise in improving inflammatory bowel diseases. The potential application of c-BIF as a biomarker for immunotherapy is explored, with a specific emphasis on its predictive and prognostic value in cancer. Suggestions are made regarding the use of humoral immune responses to cytotoxic T lymphocyte (CTL) epitope peptides that share motifs with c-BIF, proposing them as potential markers for predicting overall survival in diverse cancer patients. In conclusion, c-BIF emerges as a crucial and multifaceted determinant of human health, across anti-tumor immunity to infectious and inflammatory disease management. The manipulation of c-BIF and gut microbiota presents a promising avenue for advancing therapeutic strategies, particularly in the realm of cancer immunotherapy. Additionally, this review highlights the significance of c-BIF as potent non-self-antigens via antigenic mimicry, emphasizing the importance of robust humoral immune responses against c-BIF for preventing various diseases, including inflammatory conditions. Elevated levels of circulating antibodies against c-BIF in healthy individuals may serve as potential indicators of lower risks for malignant and non-malignant diseases.
... To succeed in cancer IO, it is important to accelerate the cancer immune cycle (Chen and Mellman 2013 mechanism by which the gut microbiota affects the tumor immune environment is complex and not yet fully understood, tumor antigenicity and adjuvanticity are associated with antitumor immune responses. Antigenicity allows antigen mimicry between bacterial and tumor antigens to prime antitumor T cells (Zitvogel et al. 2016;Derosa et al. 2021). Adjuvanticity shows that pathogen recognition receptors, also called pattern recognition receptors, are activated by the microbiome and stimulate cytokines and interferons, resulting in the modulation of the immune tonus (Zitvogel et al. 2016;Derosa et al. 2021). ...
... Antigenicity allows antigen mimicry between bacterial and tumor antigens to prime antitumor T cells (Zitvogel et al. 2016;Derosa et al. 2021). Adjuvanticity shows that pathogen recognition receptors, also called pattern recognition receptors, are activated by the microbiome and stimulate cytokines and interferons, resulting in the modulation of the immune tonus (Zitvogel et al. 2016;Derosa et al. 2021). These mechanisms facilitate the cancer immunity cycle. ...
Purpose
The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed.
Methods
We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared.
Results
Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49–1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44–1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%).
Conclusion
Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.
... Recently, the role of the microbiome has been diligently studied by which we understand the combined genetic material of microorganisms that constitute a community (Gopalakrishnan et al. 2018) on the whole human organism. Myriads of microorganisms live in the human body and cause no harm; this relationship is based on symbiosis (Lozupone 2012;Zitvogel 2016). For example, the intestinal microbiota refers to the actual collection of microorganisms themselves (Gopalakrishnan et al. 2018) and represents a complex ecosystem essential for maintaining gut homeostasis and preventing systemic inflammation (Lozupone et al. 2012;Zitvogel et al. 2016;Santacroce et al. 2020). ...
... Myriads of microorganisms live in the human body and cause no harm; this relationship is based on symbiosis (Lozupone 2012;Zitvogel 2016). For example, the intestinal microbiota refers to the actual collection of microorganisms themselves (Gopalakrishnan et al. 2018) and represents a complex ecosystem essential for maintaining gut homeostasis and preventing systemic inflammation (Lozupone et al. 2012;Zitvogel et al. 2016;Santacroce et al. 2020). Also, the role of bacteria in the respiratory system has been identified recently. ...
There have been studies on antibiotic use concerning lung cancer and its potential impact on carcinogenesis and microbiome. However, subsequent research has failed to support these associations consistently. In terms of the potential carcinogenic of antibiotics on lung cancer, the available evidence has not been sufficient to draw any definitive conclusions. Maintaining immune homeostasis and preventing pathogen invasion is critically dependent on the microbiome. The subtle balance of the body microbiota, including the lungs, is susceptible to disruption by antibiotic use. There is an association between disruptions of the lung microbiome and respiratory diseases, including lung cancer, and decreased efficacy of treatments. Patients with lung cancer are often indicated for antibiotic treatment due to respiratory infections or other comorbidities. Pulmonary infections in the area of undetected lung tumors are not uncommon. They can be an early sign of malignancy, which may explain the association between antibiotic use and lung cancer diagnosis. Antibiotic use can also affect the effectiveness of immune checkpoint inhibitor therapy. Studies suggest that antibiotic use can impair the efficacy of immune checkpoint inhibitor therapy in lung cancer patients, particularly around the time when treatment is initiated. These findings require further study, understanding underlying mechanisms, and identifying microbiota signatures associated with treatment response.
... This phenomenon can be attributed to the unique alterations in TME induced by the presence of E. coli [28,29]. The colonization of hypoxic regions by these bacteria likely creates a localized in ammatory milieu, that is conducive to attracting T cells from the peripheral circulation [30]. Once these T cells migrate into the TME, they may become sequestered due to the presence of various chemokines and cytokines that promote their retention within the tumor [24]. ...
Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial malignancy. It is characterized by insufficient infiltration of anti-tumor T lymphocytes within the tumor microenvironment (TME), rendering it an "immune cold" disease. This immune deficiency results in poor responses to immune checkpoint blockade (ICB) therapies. Recent studies have demonstrated that bacteria can proliferate within tumors and activate immune responses. Therefore, in this study, we employed Escherichia coli ( E. coli ) in combination with anti-PD-1 antibodies to treat GBM, with the aim of exploring the immune-activating potential of E. coli in GBM and its synergistic effect on anti-PD-1 therapy. Methods: The E. coli and anti-PD-1 antibody was administered intravenously and intraperitoneally, respectively. Complete blood cell count, blood biochemical analysis, hematoxylin and eosin (H&E) staining, and agar plate culture were employed to evaluate the biosafety and tumor-targeting capability of E. coli . ELISA kits were used to detect innate immune cytokines. Flow cytometry and immunofluorescence staining were used to investigate T cells. Tumor volume of tumor-bearing mice was recorded to evaluate the combined treatment efficacy. H&E staining and immunofluorescence staining were used to observe the tumor inhibition markers. Results: E. coli can specifically target into the tumor region, and activate the innate immune response in mice. Immunofluorescence staining and flow cytometry results demonstrated that the combination treatment group exhibited a significant upregulation of cytotoxic CD8 ⁺ T cells and a marked suppression of regulatory T cells compared to the control group. The expression of Ki67 was significantly downregulated, and TUNEL staining revealed an increased number of apoptotic cells in the combination treatment group. Furthermore, the tumor growth rate in the combination treatment group was significantly slower than that in the control group. Conclusions: E. coli exhibits potential antit-umor activity and can activate the innate immune response and further regulate immune cells in the tumor tissues to synergize the effect of anti-PD-1 therapy on GBM, providing new insights to enhance the efficacy of GBM immunotherapy.
... Furthermore, the complex interactions between malignant cells and the microbiota extend to their influence on the host immune system. Malignant cells and their byproducts can affect the effectiveness of adaptive immunity, which in turn influences the diversity and abundance of the microbiota [31,32]. Conversely, the microbiota itself plays a significant role in modulating immune responses against tumors, contributing to anti-tumoral surveillance mechanisms that help prevent or limit tumor growth [33]. ...
... The microbial antigens can be presented to immune cells and tumor cells, and this process can activate a response from the immune system, as effector T cells can recognize and destroy the antigen-presenting cell. As a result of antigen similarity, T lymphocytes can identify malignant cells that present similar antigenic determinants and can eliminate them [43][44][45]. Another hypothesis is that microbial residents can interact with pattern recognition receptors (PRRs) and so modulate the TIME [43,46]. ...
Simple Summary
Breast cancer continues to represent a leading cause of death among women globally. Recent studies have shown a growing link between breast cancer and the living microorganisms from the tumoral breast tissue, known as microbiota. This review looks at how the microbiota is found in healthy breast tissue and the changes observed during cancer development and progression. The microbiota has been shown to affect cancer growth, spread, and resistance to treatments by interacting with the tumor’s environment. Moreover, this review explores how different breast cancer types have distinct microbial profiles. Future studies could improve breast cancer care by endowing the microbiota as a diagnostic, prediction and treatment marker.
Abstract
Breast cancer remains one of the leading causes of death among women worldwide, and recent research highlights its growing connection to alterations in the microbiota. This review delves into the intricate relationship between microbiotas and breast cancer, exploring its presence in healthy breast tissue, its changes during cancer progression, and its considerable impact on both the tumor microenvironment (TME) and the tumor immune microenvironment (TIME). We extensively analyze how the microbiota influences cancer growth, invasion, metastasis, resistance to drugs, and the evasion of the immune system, with a special focus on its effects on the TIME. Furthermore, we investigate distinct microbial profiles associated with the four primary molecular subtypes of breast cancer, examining how the microbiota in tumor tissues compares with that in adjacent normal tissues. Emerging studies suggest that microbiotas could serve as valuable diagnostic and prognostic biomarkers, as well as targets for therapy. This review emphasizes the urgent need for further research to improve strategies for breast cancer prevention, diagnosis, and treatment. By offering a detailed examination of the microbiota’s critical role in breast cancer, this review aims to foster the development of novel microbiota-based approaches for managing the disease.
... Cancer can be affected by microbes in a variety of ways, including contact-dependent effects occurring locally at the mucosal surface or within the tumor microenvironment. The second type of effect is contact-independent effects, which are caused by the metabolites produced by microbes and the vesicles of their outer membranes that circulate in the blood [70,71]. Thus, several types of cancer may be associated with specific patterns of salivary and fecal microbiomes as well as circulating microbial DNA in blood plasma [72]. ...
Simple Summary
Patients suffering from taste disorders have been unable to find treatments in the pharmaceutical industry. In this study, a novel strategy has been presented to reduce side effects in patients suffering from cancer by administering dried miracle berries (DMBs), which contain the taste-modifying glycoprotein miraculin, as an adjuvant to medical-nutritional therapy. During a three-month pilot randomized, parallel, triple-blind, and placebo-controlled clinical trial, malnourished patients with cancer and dysgeusia received either a standard dose of DMB, a high dose of DMB, or a placebo. We analyzed the oral microbiome of patients who consumed a DMB or placebo tablet before each main meal. Patients with cancer and dysgeusia who consumed DMB regularly displayed changes to their oral microbiome, which may have contributed to the maintenance of an appropriate immune response.
Abstract
Background/Objectives: Dysgeusia contributes to the derangement of nutritional status in patients with cancer as well as worsening the quality of life. There has been a lack of effective treatments for taste disorders provided by the pharmaceutical industry. Methods: This was a pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB or placebo tablet before each main meal. Using the nanopore methodology, we analyzed the oral microbiome of patients with cancer using saliva samples. Results: All patients with cancer and dysgeusia had dysbiosis in terms of lower bacterial diversity and richness. DMB consumption was associated with changes in oral microbiome composition. Neither selected bacteria nor taste perception, type of diet, and cytokine levels were associated with mucositis. Likewise, alcohol and tobacco consumption as well as general and digestive toxicity due to systemic therapy were not associated with specific changes of the oral microbiome, according to logistic binary regression. The standard dose of DMB resulted in a lower abundance of Veillonella compared with the high DMB dose and placebo at 3 months after intervention with DMB. In particular, some species such as Streptococcus parasanguinis, Veillonella parvula, and Streptococcus mutans were less abundant in the DMB standard-dose group. Additionally, the consumption of a standard dose of DMB revealed a negative association between the concentrations of TNF-α and the abundance of species such as Streptococcus thermophilus, Streptococcus pneumoniae, Streptococcus dysgalactiae and Streptococcus agalactiae. Conclusions: Accordingly, regular DMB consumption could modify the oral microbiome in patients with cancer and dysgeusia, which may contribute to maintaining an appropriate immune response. However, as the present pilot study involved a small number of participants, further studies are necessary to draw robust conclusions from the data.
... These discoveries, viewed through the "microbe lens", offer a new perspective into the anti-cancer immune response. It has long been postulated that bacteria may produce epitopes mimicking tumor neoantigens, potentially educating lymphocytes to attack tumor cells through antigen mimicry [55]. We now appreciate that the intracellular bacteria are the source of these tumor neoantigens. ...
Simple Summary
Recent research has helped us understand more about the role of microbes in the health and disease of the lungs. The detection of microbes and microbial products in sputum may improve early lung cancer diagnosis. The monitoring of the microbiome of the lungs over time may help predict the response to and side effects of treatment. However, studies have not yet examined how diet and air pollution affect the lung microbiome and how it might be linked to the development and progression of lung cancer. By examining the lung microbiome, dietary patterns, and air pollutants, we hope to prevent and manage lung cancer in the future.
Abstract
The past several years have provided a more profound understanding of the role of microbial species in the lung. The respiratory tract is a delicate ecosystem of bacteria, fungi, parasites, and viruses. Detecting microbial DNA, pathogen-associated molecular patterns (PAMPs), and metabolites in sputum is poised to revolutionize the early diagnosis of lung cancer. The longitudinal monitoring of the lung microbiome holds the potential to predict treatment response and side effects, enabling more personalized and effective treatment options. However, most studies into the lung microbiota have been observational and have not adequately considered the impact of dietary intake and air pollutants. This gap makes it challenging to establish a direct causal relationship between environmental exposure, changes in the composition of the microbiota, lung carcinogenesis, and tumor progression. A holistic understanding of the lung microbiota that considers both diet and air pollutants may pave the way to improved prevention and management strategies for lung cancer.
... Bacteria exhibit anti-tumor immune responses through their ability for targeted, specific colonization of tumors and their immunogenic properties (65). The immunogenic capabilities of bacteria primarily manifest in their components, including peptides, polysaccharides, lipopolysaccharides, lipoteichoic acids, flagella, DNA, RNA, and others, which can be recognized by pattern recognition receptors on dendritic cells (DCs), macrophages, and neutrophils. ...
Tumors present a formidable health risk with limited curability and high mortality; existing treatments face challenges in addressing the unique tumor microenvironment (hypoxia, low pH, and high permeability), necessitating the development of new therapeutic approaches. Under certain circumstances, certain bacteria, especially anaerobes or parthenogenetic anaerobes, accumulate and proliferate in the tumor environment. This phenomenon activates a series of responses in the body that ultimately produce anti-tumor effects. These bacteria can target and colonize the tumor microenvironment, promoting responses aimed at targeting and fighting tumor cells. Understanding and exploiting such interactions holds promise for innovative therapeutic strategies, potentially augmenting existing treatments and contributing to the development of more effective and targeted approaches to fighting tumors. This paper reviews the tumor-promoting mechanisms and anti-tumor effects of the digestive tract microbiome and describes bacterial therapeutic strategies for tumors, including natural and engineered anti-tumor strategies.
... Research has established that a diverse and healthy microbiome has profound positive immunomodulatory effects. As such, it makes sense that this would extend to anti-tumour immunity [156,157]. For example, Gopalakrishnan et al. analysed the gut microbiomes of melanoma patients undergoing anti-PD-1 therapy and found that responders had a higher diversity of gut bacteria and distinct microbial compositions compared to non-responders [158]. ...
Immune checkpoint inhibitors (ICI) are a promising form of immunotherapy that have significantly changed the therapeutic landscape for many advanced cancers. They have shown unique clinical benefit against a broad range of tumour types and a strong overall impact on survival in studied patient populations. However, there are still many limitations holding back this immunotherapy from reaching its full potential as a possible curative option for advanced cancer patients. A great deal of research is being undertaken in the hope of driving advancements in this area, building a better understanding of the mechanisms behind immune checkpoint inhibition and ultimately developing more effective, safer, and wider-reaching agents. Taking into account the current literature on this topic, this review aims to explore in depth the basis of the use of ICIs in the treatment of advanced cancers, evaluate its efficacy and safety, consider its current limitations, and finally reflect on what the future holds for this very promising form of cancer immunotherapy.
... Typically, the gut microbiota consists of anaerobic bacteria and can be classified into six phyla: Firmicutes (Lactobacillus, Enterococcus, Clostridium), Bacteroidetes, Proteobacteria (Enterobacteria), Actinomycetes (Bifidobacterium), Fusobacteria, and Verrucococcus. Of the total gut microbiota, 64%, 23%, 8%, and 3% come from the first four phyla (10). There are several physiological functions performed by gut bacteria and their metabolites, including maintaining the host's gut microecological balance, enhancing immunity, regulating gut motility, affecting nutrition absorption, regulating glucose through gut hormone secretion and activating immunity, and regulating fat metabolism (11)(12)(13). ...
Background
Studies have shown that gut dysbiosis contributes to the pathophysiology of type 2 diabetes mellitus (T2DM). Identifying specific gut microbiota dysbiosis may provide insight into the pathogenesis of T2DM.
Purpose
This study investigated the causal relationship between gut microbiota and T2DM using meta-analysis and Mendelian randomization (MR).
Methods
In the first part, we searched for literature on gut microbiota and T2DM, and conducted a meta-analysis. We observed differences in glycosylated hemoglobin and fasting blood glucose levels in both groups. Second, we obtained GWAS data from genome-wide association study database 19 (GWAS). We used two-sample MR analysis to verify the forward and reverse causal associations between gut microbiota and T2DM. Additionally, we selected the European GWAS data from the European Bioinformatics Institute (EBI) as a validation set for external validation of the MR analysis. In the third part, we aimed to clarify which gut microbiota contribute to the degree of causal association between group disorders and T2DM through multivariate MR analysis and Bayesian model averaging (MR-BMA).
Results
1. According to the meta-analysis results, the glycated hemoglobin concentration in the gut probiotic intervention group was significantly lower than in the control group. Following treatment, fasting blood glucose levels in the intervention group were significantly lower than those in the control group. 2. The results of two samples MR analysis revealed that there were causal relationships between six gut microbiota and T2DM. Genus Haemophilus and order Pasteurellaceae were negatively correlated with T2DM. Genus Actinomycetes, class Melanobacteria and genus Lactobacillus were positively correlated. Reverse MR analysis demonstrated that T2DM and gut microbiota did not have any reverse causal relationship. The external validation data set showed a causal relationship between gut microbiota and T2DM. 3. Multivariate MR analysis and MR-BMA results showed that the independent genus Haemophilus collection had the largest PP.
Conclusion
Our research results suggest that gut microbiota is closely related to T2DM pathogenesis. The results of further MR research and an analysis of the prediction model indicate that a variety of gut microbiota disorders, including genus Haemophilus, are causally related to the development of T2DM. The findings of this study may provide some insight into the diagnosis and treatment of T2DM.
Systematic review registration
https://www.crd.york.ac.uk/PROSPERO
... [39,40] Components such as peptidoglycans, lipopolysaccharides, and lipoteichoic acids on the bacterial surface can be recognized by pattern recognition receptors on immune cells like dendritic cells and macrophages. [41] This recognition subsequently triggers the immune responses, effectively activating immune cells within the immunosuppressive tumor microenvironment. As a result, the specific immune recognition and elimination of tumor cells are enhanced. ...
Nanomedicine has shown promising therapeutic potential in cancer treatment, with clinically approved formulations such as Doxil® and Abraxane® already providing tangible benefits to patients. However, challenges such as low targeting efficiency and poor tumor penetration limit its application. Bacteria have emerged as promising drug delivery carriers due to their capacity for autonomous navigation and deep penetration into hypoxic tumor parenchyma. Therefore, utilizing bacteria as carriers for nanomedicine can partially overcome the limitations of anti‐tumor nanomedicine. Moreover, some bacteria, like Salmonella typhimurium and Escherichia coli, exhibit immunostimulatory and oncolytic effects and can synergistically enhance the anti‐tumor effects of nanomedicine. This article summarizes common types of bacteria and nanomedicines and their respective advantages and challenges in cancer treatment. It elaborates on various strategies for combining bacteria and nanomedicine under different administration routes, outlining the clinical progress and challenges of bacterial anti‐tumor therapy and outlooking for future applications of utilizing bacteria as carriers for nanomedicine in cancer treatment.
... However, a portion of cancer cells adapt by reducing the levels of MHC class I after BCG therapy, limiting the increases in T cells within the TME, accompanied by an enhanced immunosuppressive myeloid profile. The downregulation of HLA-I expression in bladder cancers is unlikely to result from immunoediting (immune-mediated selection of tumor cells with reduced immunogenicity), but it reflects a direct BCG-induced HLA-I loss in cancer cells [43][44][45][46][47][48][49], a part of a wide spectrum of suppressive events involving prostaglandins and elevation of PDL1 expression in bladder cancer TME [50][51][52], indicating the need for coordinated targeting of these pathways. ...
The clinical management of bladder cancer continues to present significant challenges. Bacillus Calmette–Guérin (BCG) immunotherapy remains the gold standard of treatment for non-muscle invasive bladder cancer (NMIBC), but many patients develop recurrence and progression to muscle-invasive disease (MIBC), which is resistant to BCG. This review focuses on the immune mechanisms mobilized by BCG in bladder cancer tumor microenvironments (TME), mechanisms of BCG resistance, the dual role of the BCG-triggered NFkB/TNFα/PGE2 axis in the regulation of anti-tumor and tumor-promoting aspects of inflammation, and emerging strategies to modulate their balance. A better understanding of BCG resistance will help develop new treatments and predictive biomarkers, paving the way for improved clinical outcomes in bladder cancer patients.
... Several models discuss mechanisms for the influence of the microbiome on antitumor immunosurveillance (5), particularly for explaining the relationship between gut microbiota and the efficiency of PD1 cancer immunotherapies (3). ...
Background and purpose
Extracellular electron transferring (EET) or redox bacteria employ a shuttle of flavins to transfer electrons to the oxygen in the intestinal mucosa. Although clinical studies suggest that the gut microbiome modulates the efficiency of immune checkpoint therapy in patients with cancer, the modulation mechanisms have not been well-characterized yet.
Experimental approach
In the present study, the oral gavage administration of Shewanella oneidensis MR-1 as a prototypic EET bacteria was assayed in a mouse model of lung cancer to determine the effect of EET bacterium on the efficacy of the programmed cell death protein 1 (PD1)-immune checkpoint therapy.
Findings/Results
It was indicated that in vitro EET from S. oneidensis was mediated by riboflavins that were supplied through extrinsic sources. Co-administration of S. oneidensis and anti-PD 1 antibodies represent better tumor remission compared to the single-administration of each one; however, no statistically significant change was observed in the tumor volume.
Conclusion and implications
More detailed studies are needed to definitively confirm the therapeutic effects of electrogenic bacteria in patients with cancer. Given the findings of the present study, increasing flavin compounds or EET bacteria in the intestine may provide novel strategies for modulating cancer immunotherapy.
... The intestinal microbiota was reported to correlate with chemotherapy resistance in CRC. 23 For example, Caenorhabditis elegans can influence the host response to 5-Fu. 24 The enrichment of F. nucleatum was shown to be involved in drug resistance to standard 5-Fu adjuvant chemotherapy in patients with CRC after radical resection. ...
Chemotherapy resistance is one of the main reasons for the poor prognosis of colorectal cancer (CRC). Moreover, dysbiosis of gut bacteria was found to be a specific environmental risk factor. In this study, enrichment of F. nucleatum was elucidated to be significantly associated with CRC recurrence after chemotherapy. Functional experiments showed that F. nucleatum could inhibit pyroptosis induced by chemotherapy drugs, thereby inducing chemoresistance. Furthermore, mechanistic investigation demonstrated that F. nucleatum could regulate the Hippo pathway and promote the expression of BCL2, thereby inhibiting the Caspase-3/GSDME pyroptosis-related pathway induced by chemotherapy drugs and mediating CRC cell chemoresistance. Taken together, these results validated the significant roles of F. nucleatum in CRC chemoresistance, which provided an innovative theoretical basis for the clinical diagnosis and therapy of CRC.
... The human microbiome-which includes bacteria, viruses, and fungi-varies depending on demographic factors like age, race, and environment and clinical variables like disease progression and treatment [2]. Therefore, a number of studies have analyzed the link between the human microbiome, disease progression, and cancer therapy efficacy and identified several potential correlations relevant to the diagnosis, treatment, and prognosis of various cancers [3][4][5][6][7]. ...
Microbial dysbiosis has an increasingly appreciated impact on carcinogenesis, and the cervicovaginal microbiome plays a critical role in microenvironmental inflammation. Here, we investigated the involvement of the female genital tract Peptostreptococcus species in gynecological cancer via indoleacrylic acid (IAA). IAA production from Peptostreptococcus species and the effect of bacterial culture on tumor growth in vivo were examined. The impact of IAA on cytokine production and indoleamine-2,3-dioxygenase 1 (IDO1) expression in an endometrial cancer (EC) cell line, as well as their effect on Treg and Teff cells, and M1 and M2 macrophage populations were examined in EC patients and tumor-grafted mice. Clinically, Peptostreptococcus species abundance, IAA, and IDO1 expression were verified in EC patients. The results showed that IAA production was induced in the uteri of BALB/c nude mice by Peptostreptococcus species transplantation, and the intratumoral injection of a conditioned medium from Peptostreptococcus cultures into tumor-grafted mice promoted tumor growth. IL-10 expression was upregulated by IAA; IFN-γ expression was increased by IL-10. IFN-γ induced IDO1 expression in the EC cell line. The co-culture of IDO1-expressing EC cells with peripheral blood mononuclear cells upregulated the Treg proportion and decreased the M1/M2 ratio. Clinically, P. anaerobius was more abundant amongst the uterine microbiota of EC patients than the control. The IAA, IDO1, and kynurenine/tryptophan ratios were all higher in EC tissue, and the M1/M2 ratio was lower. Our study sheds light on the link between IDO1 induction and uterine Peptostreptococcus dysbiosis and provides a potential rationale for the role of Peptostreptococcus species in immune tolerance induction in type I endometrial cancer.
... In addition, microorganisms can also act as immunostimulatory adjuvants by binding to Toll-like receptors (TLRs), activating MyD88dependent signaling pathways, inducing inflammatory responses, and participating in the differentiation of T cells to further enhance antitumor immunity (Coussens et al., 2013). Bacterial components, including peptidoglycan, lipopolysaccharide (LPS), lipophosphatidic acid (LTA), flagella, DNA, RNA, etc., promote the maturation of DCs, which in turn promote the differentiation of naive T cells into effector T cells and subsequently trigger the corresponding immune response (Zitvogel et al., 2016). LPS is present in the outer membrane of Gram-negative bacteria and is a strongly immunogenic microbe-associated molecular pattern (MAMP). ...
... Commensal microbiome proteins have the ability to cross the intestinal walls and trigger the generation of cytokines and interferons, activate T cells, and activate Toll-like receptors via the gut-lung nexus. 22 Molecular replication is the term for this process, in which tumor neoantigen-like receptors generated by gut-dwelling microbial species as part of their endogenous DNA replication processes can mimic cancer neoantigens, stimulating self-reactive T-cells and strong immune response against tumors. 23 Researchers have recently demonstrated that Bacteroidales play a major part in the stimulation of the immune system linked to ICIs. ...
Lung cancer (LC) is the most common cause of cancer‐related death worldwide and poses a severe threat to public health. Immunotherapy with checkpoint blockers has improved the outlook for advanced non‐small cell lung cancer (NSCLC) therapy. For the treatment of patients with advanced NSCLC, antibodies such as anti‐programmed death 1 (anti‐PD1), anti‐programmed death ligand 1 (anti‐PD‐L1), and anti‐cytotoxic T lymphocyte‐associated antigen 4 (anti‐CTLA‐4) are of paramount importance. Anti‐PD‐1 and anti‐PD‐L1 monoclonal antibody therapies are used to block the PD‐1/PD‐L1 pathway and identify cancerous cells to the body's defenses. Antibodies directed against CTLA‐4 (anti‐CTLA‐4) have also been shown to improve survival rates in patients with NSCLC. Currently, other immunotherapy approaches like neoadjuvant immune checkpoint inhibitors (NAICIs) and chimeric antigen receptor T‐cell (CAR‐T) therapies are applied in NSCLC patients. NAICIs are used for resectable and early stage NSCLC and CAR‐T is used to find more useful epitope sites for lung tumors and destroy cancer cells. A patient's gut microbiota might influence how their immune system reacts to NSCLC immunotherapy. The majority of intestinal microbes stimulate helper/cytotoxic T cells, induce natural killer (NK) cells, activate various toll‐like receptors (TLR), build up cluster of differentiation 8 (CD8), increase PD‐1 production, and attract chemokine receptors towards cancer cells. Thus, they serve as immune inducers in NSCLC immunotherapy. Nonetheless, certain bacteria can function as immune suppressors by inhibiting DC proliferation, stopping CD28 trafficking, restoring CD80/CD86, increasing immunological tolerance, and upsetting Th17 cells. Therefore, they are prevalent in non‐responders with NSCLC immunotherapy.
... The long-term effect of the flora on the immune system is hypothesized to be due to the phenomenon of antigen mimicry or cross-reaction: the flora crosses the intestinal barrier and stimulates T cells, thereby promoting immune system reactivity and antitumor response, and is an agent of immunosurveillance. After crossing the intestinal barrier, bacterial flora interacts with pattern-recognition receptors and stimulates the intestinal lymphatic system to produce various cytokines and interferons, thus inducing pro-inflammatory, immunostimulatory, or immunosuppressive responses [16]. ...
Context: As a flavonoid compound, kaempferol has great potential in anti-lung cancer therapy, but the mechanism of its therapeutic effect needs further exploration.
Objective: To explore the therapeutic effect of kaempferol on lung cancer, as well as its capability to regulate the gut microbiota and stimulate immune function.
Materials & methods: Twenty-four BALB/c mice were divided into four groups. The first two groups, consisting of 12 normal mice, were administered either PBS or Kaempferol (Kaem) via gavage. The remaining 12 mice, which were subcutaneously inoculated with Lewis Lung Carcinoma (LLC) cells, were similarly divided and subjected to the same treatments respectively. The inhibitory effect of kaempferol on xenograft lung cancer models was explored with in vivo experiments, the diversity of gut microbiota was investigated by 16S rDNA sequencing, and the treatment effect on immune cells was quantified using flow cytometry.
Results: Kaempferol exerted a significant inhibitory effect on xenograft lung cancer models in vivo. It effectively inhibited the proliferation of LLC cells and significantly activated cytotoxic T cells, natural killer cells, and other immune cells in mice. 16S rRNA sequencing of fecal samples from tumor-bearing mice treated with kaempferol showed a significant increase in the abundances of potentially advantageous microbial species such as c_Bacilli, o_Lactobacillales, f_Lachnospiraceae, s_uncultured_bacterium_g_Lactobacillus, g_Lactobacillus, f_Bacteroidaceae, g_Bacteroides, and s_uncultured_bacterium_g_Bacteroides, s_Bacteroides_acidifaciens. An increase in the proportions of three types of immune cells might associated with the above dominant bacterial species.
Conclusion: Kaempferol can inhibit xenograft lung cancer models. Such inhibition effect might come from the activation of T cells, NK cells, and other immune cells which are modulated by the gut microbiota.
... Prolonged exposure to antigens keeps T cells in a state of exhaustion, leading to T cell dysfunction and increasing tumor susceptibility 36 . Intestinal flora can also stimulate the sustained expression of suppressor molecules, such as PD-1, CTLA-4, and TIM-3, which promotes tumor immune evasion 37 . In addition, complement receptor C3aR deficiency promotes tumor development, which may be related to the fact that C3aR deficiency accelerates the establishment of CRC-associated flora. ...
Intestinal flora affects the maturation of the host immune system, serves as a biomarker and efficacy predictor in the immunotherapy of several cancers, and has an important role in the development of colorectal cancer (CRC). Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/dMMR CRC but performed poorly in patients with MSS/pMMR CRC. In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients. Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC. Herein, we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s). We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies. In addition, we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.
... Finally, multiple targets of cancer-immunity cycle are broken through 11 . Among them, more attention has been paid to the unmethylated CpG motifs in bacterial DNA, which are responsible for immune stimulation 81 . CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences, which can be recognized by plasmacytoid dendritic cells and TLR9-expressing B cells. ...
... Finally, multiple targets of cancer-immunity cycle are broken through 11 . Among them, more attention has been paid to the unmethylated CpG motifs in bacterial DNA, which are responsible for immune stimulation 81 . CpG oligodeoxynucleotides (ODNs) are synthetic DNA sequences, which can be recognized by plasmacytoid dendritic cells and TLR9-expressing B cells. ...
Bacteria-mediated anti-tumor therapy has received widespread attention due to its natural tumor-targeting ability and specific immune-activation characteristics. It has made significant progress in breaking the limitations of monotherapy and effectively eradicating tumors, especially when combined with traditional therapy, such as radiotherapy. According to their different biological characteristics, bacteria and their derivatives can not only improve the sensitivity of tumor radiotherapy but also protect normal tissues. Moreover, genetically engineered bacteria and bacteria-based biomaterials have further expanded the scope of their applications in radiotherapy. In this review, we have summarized relevant researches on the application of bacteria and its derivatives in radiotherapy in recent years, expounding that the bacteria, bacterial derivatives and bacteria-based biomaterials can not only directly enhance radiotherapy but also improve the anti-tumor effect by improving the tumor microenvironment (TME) and immune effects. Furthermore, some probiotics can also protect normal tissues and organs such as intestines from radiation via anti-inflammatory, anti-oxidation and apoptosis inhibition. In conclusion, the prospect of bacteria in radiotherapy will be very extensive, but its biological safety and mechanism need to be further evaluated and studied.
... Recent data report an association between the gut microbiome and ICI efficacy [12]. The immunology of the gut-lung axis is an emerging field and can be explained by antigen mimicry or cross-reactivity [13]. Microbiota antigens that pass the intestinal barrier can result in T-cell priming, stimulating cytokine and interferon production and eliciting an antitumor immune response. ...
Simple Summary
There is a lack of understanding of the pathogenesis and mechanisms accounting for the large variability in tumor response to immune checkpoint inhibition. In this study, we investigate the role and composition of the human gut microbiome in the clinical setting by integrating shotgun metagenomics and quantitative texture analysis (QTA) of CT images in NSCLC patients treated with anti-PD-L1 immunotherapy using a novel machine learning approach. Using all available parameters, the XGB machine learning system predicted therapeutic response with an accuracy of 83% and correctly separated long-term survival patients from short-term survival patients with an accuracy of 69%. Our findings show that an integrated signature of these characteristics may predict outcomes more accurately than separate measures and may have potential therapeutic implications in the future.
Abstract
This study aims to combine computed tomography (CT)-based texture analysis (QTA) and a microbiome-based biomarker signature to predict the overall survival (OS) of immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients by analyzing their CT scans (n = 129) and fecal microbiome (n = 58). One hundred and five continuous CT parameters were obtained, where principal component analysis (PCA) identified seven major components that explained 80% of the data variation. Shotgun metagenomics (MG) and ITS analysis were performed to reveal the abundance of bacterial and fungal species. The relative abundance of Bacteroides dorei and Parabacteroides distasonis was associated with long OS (>6 mo), whereas the bacteria Clostridium perfringens and Enterococcus faecium and the fungal taxa Cortinarius davemallochii, Helotiales, Chaetosphaeriales, and Tremellomycetes were associated with short OS (≤6 mo). Hymenoscyphus immutabilis and Clavulinopsis fusiformis were more abundant in patients with high (≥50%) PD-L1-expressing tumors, whereas Thelephoraceae and Lachnospiraceae bacterium were enriched in patients with ICI-related toxicities. An artificial intelligence (AI) approach based on extreme gradient boosting evaluated the associations between the outcomes and various clinicopathological parameters. AI identified MG signatures for patients with a favorable ICI response and high PD-L1 expression, with 84% and 79% accuracy, respectively. The combination of QTA parameters and MG had a positive predictive value of 90% for both therapeutic response and OS. According to our hypothesis, the QTA parameters and gut microbiome signatures can predict OS, the response to therapy, the PD-L1 expression, and toxicity in NSCLC patients treated with ICI, and a machine learning approach can combine these variables to create a reliable predictive model, as we suggest in this research.
Radiotherapy is a widely used cancer treatment that utilizes powerful radiation to destroy cancer cells and shrink tumors. While radiation can be beneficial, it can also harm the healthy tissues surrounding the tumor. Recent research indicates that the microbiota, the collection of microorganisms in our body, may play a role in influencing the effectiveness and side effects of radiation therapy. Studies have shown that specific species of bacteria living in the stomach can influence the immune system’s response to radiation, potentially increasing the effectiveness of treatment. Additionally, the microbiota may contribute to adverse effects like radiation-induced diarrhea. A potential strategy to enhance radiotherapy outcomes and capitalize on the microbiome involves using probiotics. Probiotics are living microorganisms that offer health benefits when consumed in sufficient quantities. Several studies have indicated that probiotics have the potential to alter the composition of the gut microbiota, resulting in an enhanced immune response to radiation therapy and consequently improving the efficacy of the treatment. It is important to note that radiation can disrupt the natural balance of gut bacteria, resulting in increased intestinal permeability and inflammatory conditions. These disruptions can lead to adverse effects such as diarrhea and damage to the intestinal lining. The emerging field of radiotherapy microbiome research offers a promising avenue for optimizing cancer treatment outcomes. This paper aims to provide an overview of the human microbiome and its role in augmenting radiation effectiveness while minimizing damage.
Dysgeusia contributes to the derangement of nutritional status in patients with cancer, as well as worsening the quality of life. The pharmaceutical industry has failed to provide effective treatments for patients suffering from taste disorders. The present study provided a novel strategy to reduce side effects in patients with cancer through the administration of a novel food supplement approved by the European Union, Dried Miracle Berries (DMB), containing the taste-modifying glycoprotein miraculin, as an adjuvant to medical-nutritional treatment. This was done in a pilot randomized, parallel, triple-blind, and placebo-controlled intervention clinical trial in which 31 malnourished patients with cancer and dysgeusia receiving antineoplastic treatment were randomized into three arms [standard dose of DMB (150 mg DMB/tablet), high dose of DMB (300 mg DMB/tablet) or placebo (300 mg freeze-dried strawberry)] for three months. Patients consumed a DMB or placebo tablet before each main meal. Using the Nanopore methodology, we analyzed the oral microbiome of patients with cancer using saliva samples. All patients with cancer and dysgeusia had dysbiosis in terms of lower bacterial diversity and richness. DMB consumption was associated with changes in oral microbiome composition. Neither selected bacteria, nor taste perception, type of diet, and cytokine levels were associated with mucositis. Likewise, alcohol and tobacco consumption as well as general and digestive toxicity due to systemic therapy was not associated to specific changes of the oral microbiota. The standard dose of DMB resulted in a greater relative abundance of Enterococcus and a lower abundance of Veillonella compared with the high DMB dose and placebo. In particular, some species such as Granulicatella elegans , Granulicatella adiacens , Streptococcus mutans , and Gemella morbillorum showed higher relative abundances in the DMB standard-dose group; in contrast, Streptococcus parasanguinis , Veillonella parvula , Streptococcus australis , and Streptococcus cristatus were less abundant. Additionally, the consumption of a standard dose of DMB revealed a negative association between the concentrations of TNF-α and the abundance of species such as Streptococcus thermophilus , Streptococcus pneumoniae , Streptococcus dysgalactiae and Streptococcus agalactiae. Accordingly, regular DMB consumption changed the oral microbiome in patients with cancer and dysgeusia, which may contribute to maintaining an appropriate immune response without changing taste perception. However, as the present pilot study involved a small number of participants, further studies are necessary draw robust conclusions from the data.
Highlights
Patients with cancer and dysgeusia exhibit a dysbiotic state in terms of bacterial diversity and richness.
The regular consumption of a standard dose of Dried Miracle Berries (DMB), rich in miraculin, before each main meal for three months as an adjuvant to medical-nutritional treatment, improves the oral microbiome composition in malnourished patients with cancer and dysgeusia.
Several species i.e., Granulicatella elegans , Granulicatella adiacens , Streptococcus mutans , and Gemella morbillorum , show higher relative abundances in the DMB standard-dose group; in contrast, Streptococcus parasanguinis , Veillonella parvula , Streptococcus australis , and Streptococcus cristatus are less abundant
DMB consumption is negatively associated with some species of Streptococcus and TNF-α concentrations in malnourished patients with cancer and dysgeusia.
Neither of the highly represented bacteria are associated with the presence or absence of mucositis, digestive toxicity, or tobacco use and alcohol consumption or a change in taste perception at the end of the intervention.
The gut microbiota influences the effectiveness and side effects of cancer treatments, particularly immunotherapy and associated immune-related complications. This important involvement of the microbiome is supported by the patients receiving antibiotics responding poorly to immunotherapy. Relatively few research has examined the underlying processes, and until recently, data regarding the detection of the microbial organisms that trigger these effects were inconsistent. Since then, a deeper comprehension of the processes of action and taxonomic classification of the relevant species has been attained. It's been demonstrated that certain bacterial species can enhance the body’s reaction to immune checkpoint inhibitors through the release of distinct metabolites or products. Nonetheless, in certain patients who are not responding, Gram-negative bacteria may have a dominating suppressive impact. Patients' propensity to react to immunotherapy can be somewhat accurately predicted by machine learning techniques based on their microbiome makeup. Consequently, there has been an increase in interest in modifying the microbiome makeup to enhance patient reaction to medication. Clinical proof-of-concept studies demonstrate that dietary modifications or fecal microbiota transplantation (FMT) might be used therapeutically to increase the efficacy of immunotherapy in cancer patients. Current developments and new approaches for microbiota-based cancer treatments have been emphasized. In conclusion, preclinical research on animals and human clinical trials has made tremendous progress in our understanding of the function of the gut microbiome in health and illness. These investigations have shed light on the effects of food, FMT, probiotics, prebiotics, and microbiome-disease connections. However, there are still a lot of issues and restrictions that must be resolved before this research can be used in real-world clinical settings.
Tumor immune microenvironment (TIME) consists of intra-tumor immunological components and plays a significant role in tumor initiation, progression, metastasis, and response to therapy. Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized the cancer treatment paradigm. Although CAR-T cell immunotherapy has emerged as a successful treatment for hematologic malignancies, it remains a conundrum for solid tumors. The heterogeneity of TIME is responsible for poor outcomes in CAR-T cell immunotherapy against solid tumors. The advancement of highly sophisticated technology enhances our exploration in TIME from a multi-omics perspective. In the era of machine learning, multi-omics studies could reveal the characteristics of TIME and its immune resistance mechanism. Therefore, the clinical efficacy of CAR-T cell immunotherapy in solid tumors could be further improved with strategies that target unfavorable conditions in TIME. Herein, this review seeks to investigate the factors influencing TIME formation and propose strategies for improving the effectiveness of CAR-T cell immunotherapy through a multi-omics perspective, with the ultimate goal of developing personalized therapeutic approaches.
The growing field of gut–brain axis research offers significant potential to revolutionize medical practices and improve human well-being. Neutrophils have emerged as key players in gut–brain inflammation, contributing to the relocation of inflammatory cells from the gut to the brain and exacerbating neuroinflammation in conditions, such as inflammatory bowel disease and neurodegenerative diseases. The intricate network of molecular and functional connections that interlinks the brain with the gastrointestinal system is characterized by complex signaling pathways. Understanding the complex interplay among the microbiota, gut, and brain offers unparalleled opportunities to develop novel therapeutic interventions for neurological disorders and improve overall health outcomes. The aim of this review was to comprehensively summarize current knowledge and future perspectives regarding the multifaceted role of neutrophils and their impact on the neuroimmune dynamics in the context of the gut–brain axis.
Systemic therapies using programmed death-1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors have demonstrated commendable efficacy in some patients with advanced hepatocellular carcinoma (HCC); however, other individuals do not respond favorably. Hence, identifying the biomarkers, the prognostic factors, and their underlying mechanisms is crucial. In this review, we summarized the latest advancements in this field. Within the tumor microenvironment, PD-L1 expression is commonly utilized to predict response. Moreover, the characteristics of tumor-infiltrating lymphocytes are associated with the effectiveness of immunotherapy. Preclinical studies have identified stimulatory dendritic cells, conventional dendritic cells, and macrophages as potential biomarkers. The emergence of single-cell sequencing and spatial transcriptomics has provided invaluable insights into tumor heterogeneity through the lens of single-cell profiling and spatial distribution. With the widespread adoption of next-generation sequencing, certain genomic characteristics, including tumor mutational burden, copy number alterations, specific genes (TP53, CTNNB1, and GZMB), and signaling pathways (WNT/β-catenin) have been found to correlate with prognosis. Furthermore, clinical features such as tumor size, number, and metastasis status have demonstrated prognostic value. Notably, common indicators such as the Child-Pugh score and Eastern Cooperative Oncology Group score, which are used in patients with liver diseases, have shown potential. Similarly, commonly employed laboratory parameters such as baseline transforming growth factor beta, lactate dehydrogenase, dynamic changes in alpha-fetoprotein (AFP) and abnormal prothrombin, CRAFITY score (composed of C-reactive protein and AFP), and immune adverse events have been identified as predictive biomarkers. Novel imaging techniques such as EOB-MRI and PET/CT employing innovative tracers also have potential. Moreover, liquid biopsy has gained widespread use in biomarker studies owing to its non-invasive, convenient, and highly reproducible nature, as well as its dynamic monitoring capabilities. Research on the gut microbiome, including its composition, dynamic changes, and metabolomic analysis, has gained considerable attention. Efficient biomarker discovery relies on continuous updating of treatment strategies. Next, we summarized recent advancements in clinical research on HCC immunotherapy and provided an overview of ongoing clinical trials for contributing to the understanding and improvement of HCC immunotherapy.
Supplementary Information
The online version contains supplementary material available at 10.1186/s40364-023-00535-z.
Studies in preclinical models support that the gut microbiota play a critical role in the development and progression of colorectal cancer (CRC). Specific microbial species and their corresponding virulence factors or associated small molecules can contribute to CRC development and progression either via direct effects on the neoplastic transformation of epithelial cells or through interactions with the host immune system. Induction of DNA damage, activation of Wnt/β-catenin and NF-κB proinflammatory pathways, and alteration of the nutrient's availability and the metabolic activity of cancer cells are the main mechanisms by which the microbiota contribute to CRC. Within the tumor microenvironment, the gut microbiota alter the recruitment, activation, and function of various immune cells, such as T cells, macrophages, and dendritic cells. Additionally, the microbiota shape the function and composition of cancer-associated fibroblasts and extracellular matrix components, fashioning an immunosuppressive and pro-tumorigenic niche for CRC. Understanding the complex interplay between gut microbiota and tumorigenesis can provide therapeutic opportunities for the prevention and treatment of CRC.
Hematopoietic stem cells (HSCs) are the source for all blood cells, including immune cells, and they interact dynamically with the immune system. This chapter will explore the nature of stem cells, particularly HSCs, in the context of their immune microenvironment. The dynamic interactions between stem cells and the immune system can have profound implications for current and future therapies, particularly regarding a potential “immune-privileged” HSC microenvironment. Immune/stem cell interactions change during times of stress and injury. Recent advances in cancer immunotherapy have overturned the long-standing belief that, being derived from the self, cancer cells should be immunotolerant. Instead, an immunosurveillance system recognizes and eliminates emergent pre-cancerous cells. Only in the context of a failing immunosurveillance system does cancer fully develop. Combined with the knowledge that stem cells or their unique properties can be critically important for cancer initiation, persistence, and resistance to therapy, understanding the unique immune properties of stem cells will be critical for the development of future cancer therapies. Accordingly, the therapeutic implications for leukemic stem cells (LSCs) inheriting an immune-privileged state from HSCs will be discussed. Through their dynamic interactions with a diverse immune system, stem cells serve as the light and dark root of cancer prevention vs. development.
Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.
Context
The association between the gut microbiota and thyroid cancer remains controversial.
Objective
We aimed to systematically investigate the interactive causal relationships between the abundance and metabolism pathways of gut microbiota and thyroid cancer.
Methods
We leveraged genome-wide association studies for the abundance of 211 microbiota taxa from the MiBioGen study (N = 18,340), 205 microbiota metabolism pathways from the Dutch Microbiome Project (N = 7738), and thyroid cancer from the Global Biobank Meta-analysis Initiative (N cases = 6699 and N participants = 1,620,354). We performed a bidirectional Mendelian randomization (MR) to investigate the causality from microbiota taxa and metabolism pathways to thyroid cancer, and vice versa. We performed a systematic review of previous observational studies and compared MR results with observational findings.
Results
Eight taxa and twelve metabolism pathways had causal effects on thyroid cancer, where RuminococcaceaeUCG004 genus (P = 0.001), Streptococcaceae family (P = 0.016), Olsenella genus (P = 0.029), ketogluconate metabolism pathway (P = 0.003), pentose phosphate pathway (P = 0.016), and L-arginine degradation II in AST pathway (P = 0.0007) were supported by sensitivity analyses. Conversely, thyroid cancer had causal effects on three taxa and two metabolism pathways, where the Holdemanella genus (P = 0.015) was supported by sensitivity analyses. The Proteobacteria phylum, Streptococcaceae family, Ruminococcus2 genus, and Holdemanella genus were significantly associated with thyroid cancer in both the systematic review and MR, while the other 121 significant taxa in observational results were not supported by MR.
Discussions
These findings implicated the potential role of host-microbiota crosstalk in thyroid cancer, while the discrepancy among observational studies calls for further investigations.
Tumor-resident Lactobacillus iners confer chemoradiation resistance through lactate-induced metabolic rewiring Graphical abstract Highlights d L. iners is associated with poor tumor response to chemoradiation d L. iners primes tumor metabolism for increased L-lactate production d Other lactic acid bacteria are associated with poor survival in other cancer types In brief Colbert et al. describe how tumoral Lactobacillus iners strongly predict poor chemoradiation response and survival for patients with cervical cancer. Further, L. iners, and potentially other obligate L-lactate-producing lactic acid bacteria, appear to rewire tumor metabolism and could serve as biomarkers or therapeutic targets in multiple cancer types. SUMMARY Tumor microbiota can produce active metabolites that affect cancer and immune cell signaling, metabolism, and proliferation. Here, we explore tumor and gut microbiome features that affect chemoradiation response in patients with cervical cancer using a combined approach of deep microbiome sequencing, targeted bacterial culture, and in vitro assays. We identify that an obligate L-lactate-producing lactic acid bacterium found in tumors, Lactobacillus iners, is associated with decreased survival in patients, induces chemo-therapy and radiation resistance in cervical cancer cells, and leads to metabolic rewiring, or alterations in multiple metabolic pathways, in tumors. Genomically similar L-lactate-producing lactic acid bacteria commensal to other body sites are also significantly associated with survival in colorectal, lung, head and neck, and skin cancers. Our findings demonstrate that lactic acid bacteria in the tumor microenvironment can alter tumor metabolism and lactate signaling pathways, causing therapeutic resistance. Lactic acid bacteria could be promising therapeutic targets across cancer types.
Although there is little direct evidence supporting that stress affects cancer incidence, it does influence the evolution, dissemination and therapeutic outcomes of neoplasia, as shown in human epidemiological analyses and mouse models. The experience of and response to physiological and psychological stressors can trigger neurological and endocrine alterations, which subsequently influence malignant (stem) cells, stromal cells and immune cells in the tumour microenvironment, as well as systemic factors in the tumour macroenvironment. Importantly, stress-induced neuroendocrine changes that can regulate immune responses have been gradually uncovered. Numerous stress-associated immunomodulatory molecules (SAIMs) can reshape natural or therapy-induced antitumour responses by engaging their corresponding receptors on immune cells. Moreover, stress can cause systemic or local metabolic reprogramming and change the composition of the gastrointestinal microbiota which can indirectly modulate antitumour immunity. Here, we explore the complex circuitries that link stress to perturbations in the cancer-immune dialogue and their implications for therapeutic approaches to cancer.
Background
In case of locally advanced and/or non-metastatic unresectable esophageal cancer, definitive chemoradiotherapy (CRT) delivering 50 Gy in 25 daily fractions in combination with platinum-based regimen remains the standard of care resulting in a 2-year disease-free survival of 25% which deserves to be associated with new systemic strategies. In recent years, several immune checkpoint inhibitors (anti-PD1/anti-PD-L1, anti-Program-Death 1/anti-Program-Death ligand 1) have been approved for the treatment of various solid malignancies including metastatic esophageal cancer. As such, we hypothesized that the addition of an anti-PD-L1 to CRT would provide clinical benefit for patients with locally advanced oesophageal cancer. To assess the efficacy of the anti-PD-L1 durvalumab in combination with CRT and then as maintenance therapy we designed the randomized phase II ARION (Association of Radiochemotherapy with Immunotherapy in unresectable Oesophageal carciNoma- UCGI 33/PRODIGE 67).
Methods
ARION is a multicenter, open-label, randomized, comparative phase II trial. Patients are randomly assigned in a 1:1 ratio in each arm with a stratification according to tumor stage, histology and centre. Experimental arm relies on CRT with 50 Gy in 25 daily fractions in combination with FOLFOX regimen administrated during and after radiotherapy every two weeks for a total of 6 cycles and durvalumab starting with CRT for a total of 12 infusions. Standard arm is CRT alone. Use of Intensity Modulated radiotherapy is mandatory.
The primary endpoint is to increase progression-free survival at 12 months from 50 to 68% (HR = 0.55) (power 90%; one-sided alpha-risk, 10%). Progression will be defined with central external review of imaging.
Ancillary studies are planned
PD-L1 Combined Positivity Score on carcinoma cells and stromal immune cells of diagnostic biopsy specimen will be correlated to disease free survival. The study of gut microbiota will aim to determine if baseline intestinal bacteria correlates with tumor response. Proteomic analysis on blood samples will compare long-term responder after CRT with durvalumab to non-responder to identify biomarkers.
Conclusion
Results of the present study will be of great importance to evaluate the impact of immunotherapy in combination with CRT and decipher immune response in this unmet need clinical situation.
Trial registration
ClinicalTrials.gov, NCT: 03777813.Trial registration date: 5 th December 2018.
Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.
CD4 T cells secreting IL-10 or IL-17 are frequent at mucosal sites, where their equilibrium is important for simultaneously maintaining tolerance and immunity to the resident microbiota. The mode of action of these cells, however, is as yet incompletely understood. In this study, we have combined ex vivo analysis of CD4 T cells producing IL-10 or/and IL-17 with assessment of clonal populations isolated ex vivo using a cytokine catch assay. We found that circulating CD4 T cells secreting IL-10 or/and IL-17 ex vivo include both conventional FOXP3- CD4 T cells and FOXP3+ Helios- Treg. Upon assessment of clonal populations derived from single ex vivo isolated cytokine secreting cells, we found that IL-10 or/and IL-17 secreting cells prevalently secrete one or the other cytokine depending on the type of stimulation, the time after stimulation and the presence of microbial products. Namely, IL-10 secretion by clonal cells was prevalent at early time points after TCR mediated stimulation, was independent of co-stimulation and was increased in the presence of the microbial fermentation product butyrate. In contrast, IL-17 secretion was higher at later time points after TCR mediated stimulation and in the presence of co-stimulatory signals. Taken together, these results provide insights into the mechanisms that, through modulation of cytokine secretion depending on conditions, allow IL-10 and IL-17 producing CD4 T cells to contribute to maintain tolerance to microbes locally, while retaining the ability to participate in protective immune responses at distant sites.
Lymphodepletion with total body irradiation (TBI) increases the efficacy of adoptively transferred tumor-specific CD8 + T cells by depleting inhibitory lymphocytes and increasing homeostatic cytokine levels. We found that TBI augmented the function of adoptively transferred CD8 + T cells in mice genetically deficient in all lym-phocytes, indicating the existence of another TBI mechanism of action. Additional investigation revealed com-mensal gut microflora in the mesenteric lymph nodes and elevated LPS levels in the sera of irradiated mice. These findings correlated with increased dendritic cell activation and heightened levels of systemic inflam-matory cytokines. Reduction of host microflora using antibiotics, neutralization of serum LPS using poly-myxin B, or removal of LPS signaling components using mice genetically deficient in CD14 and TLR4 reduced the beneficial effects of TBI on tumor regression. Conversely, administration of microbial ligand–containing serum or ultrapure LPS from irradiated animals to nonirradiated antibody-lymphodepleted mice enhanced CD8 + T cell activation and improved tumor regression. Administration of ultrapure LPS to irradiated animals further enhanced the number and function of the adoptively transferred cells, leading to long-term cure of mice with large B16F10 tumors and enhanced autoimmune vitiligo. Thus, disruption of the homeostatic balance between the host and microbes can enhance cell-based tumor immunotherapy.
Autoimmune diseases, such as systemic lupus erythematosus (SLE), are caused by a complex interaction of environmental-, genetic-, and sex-related factors. Although SLE has traditionally been considered independent from the microbiota, recent work published during the last 5 years suggests a strong connection between SLE and the composition of our gut commensals as one of the main environmental factors linked to this disease. Preliminary data have evidenced that (i) interaction of certain microbial-derived molecules with specific cell receptors and (ii) the influence of certain commensal microorganisms over specific immune cell subsets plays an important role in the pathogenesis of SLE and SLE-like diseases. In addition, epigenetic changes driven by certain microbial groups have been recently proposed as an additional link between gut microbiota and SLE. As immune responses elicited against commensal bacteria are deeply dependent on the composition of the latter, and as microbial populations can be modified by dietary interventions, identifying the precise gut microorganisms responsible for worsening the SLE symptoms is of crucial importance for this and other SLE-related diseases, including antiphospholipid syndrome or lupus nephritis. In this minireview, the current knowledge on the relationships between microbes and SLE and SLE-related diseases is compiled and discussed.
In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic
bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved
is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the
blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2–encoded type III secretion system and on
decreased β-catenin–dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated
serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding
the GVB may provide new insights into the regulation of the gut-liver axis.
T cell infiltration of solid tumors is associated with favorable patient outcomes, yet the mechanisms underlying variable
immune responses between individuals are not well understood. One possible modulator could be the intestinal microbiota. We
compared melanoma growth in mice harboring distinct commensal microbiota and observed differences in spontaneous antitumor
immunity, which were eliminated upon cohousing or after fecal transfer. Sequencing of the 16S ribosomal RNA identified Bifidobacterium as associated with the antitumor effects. Oral administration of Bifidobacterium alone improved tumor control to the same degree as programmed cell death protein 1 ligand 1 (PD-L1)–specific antibody therapy
(checkpoint blockade), and combination treatment nearly abolished tumor outgrowth. Augmented dendritic cell function leading
to enhanced CD8+ T cell priming and accumulation in the tumor microenvironment mediated the effect. Our data suggest that manipulating the
microbiota may modulate cancer immunotherapy.
Antibodies targeting CTLA-4 have been successfully used as cancer immunotherapy. We find that the antitumor effects of CTLA-4
blockade depend on distinct Bacteroides species. In mice and patients, T cell responses specific for B. thetaiotaomicron or B. fragilis were associated with the efficacy of CTLA-4 blockade. Tumors in antibiotic-treated or germ-free mice did not respond to CTLA
blockade. This defect was overcome by gavage with B. fragilis, by immunization with B. fragilis polysaccharides, or by adoptive transfer of B. fragilis–specific T cells. Fecal microbial transplantation from humans to mice confirmed that treatment of melanoma patients with
antibodies against CTLA-4 favored the outgrowth of B. fragilis with anticancer properties. This study reveals a key role for Bacteroidales in the immunostimulatory effects of CTLA-4 blockade.
Many bacteria causing persistent infections produce toxins whose mechanisms of action indicate that they could have a role in carcinogenesis. Some toxins, like CDT and colibactin, directly attack the genome by damaging DNA whereas others, as for example CNF1, CagA and BFT, impinge on key eukaryotic processes, such as cellular signalling and cell death. These bacterial toxins, together with other less known toxins, mimic carcinogens and tumour promoters. The aim of this review is to fulfil an up-to-date analysis of toxins with carcinogenic potential that have been already correlated to human cancers. Bacterial toxins-induced carcinogenesis represents an emerging aspect in bacteriology and its significance is increasingly recognized.
How dying tumor cells get noticed
Besides killing tumor cells directly, some chemotherapies, such as anthracyclines, also activate the immune system to kill tumors. Vacchelli et al. discovered that in mice, anthracycline-induced antitumor immunity requires immune cells to express the protein formyl peptide receptor 1 (FPR1). Dendritic cells (DCs) near tumors expressed especially high amounts of FPR1. DCs normally capture fragments of dying tumor cells and use them to activate nearby T cells to kill tumors, but DCs lacking FPR1 failed to do this effectively. Individuals with breast or colon cancer expressing a variant of FPR1 and treated with anthracyclines showed poor metastasis-free and overall survival. Thus, FPR1 may affect anti-tumor immunity in people, too.
Science , this issue p. 972
Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune-privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. Our findings not only have implications for the etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes might be a more common trigger of autoimmune diseases than is currently appreciated.
Copyright © 2015 Elsevier Inc. All rights reserved.
Intravesical Bacillus Calmette–Guerin (BCG) vaccine is the preferred first line treatment for non-muscle invasive bladder carcinoma (NMIBC) in order to prevent recurrence and progression of cancer. There is ongoing need for the rational selection of i) BCG dose, ii) frequency of BCG administration along with iii) synergistic adjuvant therapy and iv) a reliable set of biochemical markers relevant to tumor response. In this review we evaluate cellular and molecular markers pertinent to the immunological response triggered by the BCG instillation and respective mathematical models of the treatment. Specific examples of markers include diverse immune cells, genetic polymorphisms, miRNAs, epigenetics, immunohistochemistry and molecular biology ‘beacons’ as exemplified by cell surface proteins, cytokines, signaling proteins and enzymes. We identified tumor associated macrophages (TAMs), human leukocyte antigen (HLA) class I, a combination of Ki-67/CK20, IL-2, IL-8 and IL-6/IL-10 ratio as the most promising markers for both pre-BCG and post-BCG treatment suitable for the simulation studies.
The intricate and patient-specific nature of these data warrants the use of powerful multi-parametral mathematical methods in combination with molecular/cellular biology insight and clinical input.
E. coli is a major cause of life-threatening infections in patients with neutropenia, particularly those receiving chemotherapy for the treatment of cancer. In most cases, these infections originate from opportunistic strains living within the patient's gastrointestinal tract which then translocate to major organ systems. There are no animal models that faithfully recapitulate these infections, and, as such, the host or bacterial factors that govern this process remain unidentified. We present here a novel model of chemotherapy-induced bacterial translocation of E. coli. Oral gavage of BALB/c mice with a clinical isolate of extraintestinal pathogenic E. coli (ExPEC) leads to stable and long-term colonization of the murine intestine. Following the induction of neutropenia with the chemotherapeutic drug cyclophosphamide, ExPEC translocate from the intestine to the lungs, liver, spleen, and kidneys with concomitant morbidity in infected animals. Translocation can also occur in mice bearing mammary tumors, even in the absence of chemotherapy. Translocation of ExPEC is also associated with an increase of the diversity of bacterial DNA detected in the blood. This is the first report of a chemotherapy-based animal model of ExPEC translocation in cancerous mice, a system that can be readily used to identify important virulence factors for this process.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
Rates of colon cancer are much higher in African Americans (65:100,000) than in rural South Africans (<5:100,000). The higher rates are associated with higher animal protein and fat, and lower fibre consumption, higher colonic secondary bile acids, lower colonic short-chain fatty acid quantities and higher mucosal proliferative biomarkers of cancer risk in otherwise healthy middle-aged volunteers. Here we investigate further the role of fat and fibre in this association. We performed 2-week food exchanges in subjects from the same populations, where African Americans were fed a high-fibre, low-fat African-style diet and rural Africans a high-fat, low-fibre western-style diet, under close supervision. In comparison with their usual diets, the food changes resulted in remarkable reciprocal changes in mucosal biomarkers of cancer risk and in aspects of the microbiota and metabolome known to affect cancer risk, best illustrated by increased saccharolytic fermentation and butyrogenesis, and suppressed secondary bile acid synthesis in the African Americans.
Increasing evidence suggests that the composition of the human gut microbiome is important in the etiology of human diseases; however, the personal factors that influence the gut microbiome composition are poorly characterized. Animal models point to sex hormone-related differentials in microbiome composition. In this study, we investigated the relationship of sex, body mass index (BMI) and dietary fiber intake with the gut microbiome in 82 humans. We sequenced fecal 16S rRNA genes by 454 FLX technology, then clustered and classified the reads to microbial genomes using the QIIME pipeline. Relationships of sex, BMI, and fiber intake with overall gut microbiome composition and specific taxon abundances were assessed by permutational MANOVA and multivariate logistic regression, respectively. We found that sex was associated with the gut microbiome composition overall (p=0.001). The gut microbiome in women was characterized by a lower abundance of Bacteroidetes (p=0.03). BMI (>25 kg/m2
vs. <25 kg/m2) was associated with the gut microbiome composition overall (p=0.05), and this relationship was strong in women (p=0.03) but not in men (p=0.29). Fiber from beans and from fruits and vegetables were associated, respectively, with greater abundance of Actinobacteria (p=0.006 and false discovery rate adjusted q=0.05) and Clostridia (p=0.009 and false discovery rate adjusted q=0.09). Our findings suggest that sex, BMI, and dietary fiber contribute to shaping the gut microbiome in humans. Better understanding of these relationships may have significant implications for gastrointestinal health and disease prevention.
The microbiota is considered to be an important factor influencing the pathogenesis of autoimmunity at both barrier sites and internal organs. Impinging on innate and adaptive immunity, commensals exert protective or detrimental effects on various autoimmune animal models. Human microbiome studies of autoimmunity remain largely descriptive, but suggest a role for dysbiosis in autoimmune disease. Humanized gnotobiotic approaches have advanced our understanding of immune-commensal interactions, but little is known about the mechanisms in autoimmunity. We propose that, similarly to infectious agents, the microbiota mediates autoimmunity via bystander activation, epitope spread, and, particularly under homeostatic conditions, via crossreactivity. This review presents an overview of the current literature concluding with outstanding questions in this field.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Multiple factors have been shown to alter intestinal microbial diversity. It remains to be seen, however, how multiple collective pressures impact the activity in the gut environment and which, if any, is positioned as a dominant driving factor determining the final metabolic outcomes. Here, we describe the results of a metabolome-wide scan of gut microbiota in 18 subjects with systemic lupus erythematosus (SLE) and 17 healthy control subjects and demonstrate a statistically significant difference (p < 0.05) between the two groups. Healthy controls could be categorized (p < 0.05) based on their body mass index (BMI), whereas individuals with SLE could not. We discuss the prevalence of SLE compared with BMI as the dominant factor that regulates gastrointestinal microbial metabolism and provide plausible explanatory causes. Our results uncover novel perspectives with clinical relevance for human biology. In particular, we rank the importance of various pathophysiologies for gut homeostasis.
Background:
Immune checkpoint inhibitors are effective cancer treatments, but molecular determinants of clinical benefit are unknown. Ipilimumab and tremelimumab are antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4). Anti-CTLA-4 treatment prolongs overall survival in patients with melanoma. CTLA-4 blockade activates T cells and enables them to destroy tumor cells.
Methods:
We obtained tumor tissue from patients with melanoma who were treated with ipilimumab or tremelimumab. Whole-exome sequencing was performed on tumors and matched blood samples. Somatic mutations and candidate neoantigens generated from these mutations were characterized. Neoantigen peptides were tested for the ability to activate lymphocytes from ipilimumab-treated patients.
Results:
Malignant melanoma exomes from 64 patients treated with CTLA-4 blockade were characterized with the use of massively parallel sequencing. A discovery set consisted of 11 patients who derived a long-term clinical benefit and 14 patients who derived a minimal benefit or no benefit. Mutational load was associated with the degree of clinical benefit (P=0.01) but alone was not sufficient to predict benefit. Using genomewide somatic neoepitope analysis and patient-specific HLA typing, we identified candidate tumor neoantigens for each patient. We elucidated a neoantigen landscape that is specifically present in tumors with a strong response to CTLA-4 blockade. We validated this signature in a second set of 39 patients with melanoma who were treated with anti-CTLA-4 antibodies. Predicted neoantigens activated T cells from the patients treated with ipilimumab.
Conclusions:
These findings define a genetic basis for benefit from CTLA-4 blockade in melanoma and provide a rationale for examining exomes of patients for whom anti-CTLA-4 agents are being considered. (Funded by the Frederick Adler Fund and others.).
Some of the anti-neoplastic effects of anthracyclines in mice originate from the induction of innate and T cell-mediated anticancer immune responses. Here we demonstrate that anthracyclines stimulate the rapid production of type I interferons (IFNs) by malignant cells after activation of the endosomal pattern recognition receptor Toll-like receptor 3 (TLR3). By binding to IFN-[alpha] and IFN-[beta] receptors (IFNARs) on neoplastic cells, type I IFNs trigger autocrine and paracrine circuitries that result in the release of chemokine (C-X-C motif) ligand 10 (CXCL10). Tumors lacking Tlr3 or Ifnar failed to respond to chemotherapy unless type I IFN or Cxcl10, respectively, was artificially supplied. Moreover, a type I IFN-related signature predicted clinical responses to anthracycline-based chemotherapy in several independent cohorts of patients with breast carcinoma characterized by poor prognosis. Our data suggest that anthracycline-mediated immune responses mimic those induced by viral pathogens. We sur
T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4(+) T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.
The tremendous clinical success of checkpoint blockers illustrates the potential of reestablishing latent immunosurveillance for cancer therapy. Although largely neglected in the clinical practice, accumulating evidence indicates that the efficacy of conventional and targeted anticancer agents does not only involve direct cytostatic/cytotoxic effects, but also relies on the (re)activation of tumor-targeting immune responses. Chemotherapy can promote such responses by increasing the immunogenicity of malignant cells, or by inhibiting immunosuppressive circuitries that are established by developing neoplasms. These immunological "side" effects of chemotherapy are desirable, and their in-depth comprehension will facilitate the design of novel combinatorial regimens with improved clinical efficacy.
The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.
Bacterial dysbiosis was previously described in human malignancies. In a recent animal model, tumour susceptibility was transmitted using faecal transplantation. Our aim was to evaluate possible association between antibiotic exposure and cancer risk.
We conducted nested case-control studies for 15 common malignancies using a large population-based electronic medical record database. Cases were defined as those with any medical code for the specific malignancy. Individuals with familial cancer syndromes were excluded. For every case, four eligible controls matched on age, sex, practice site and duration of follow-up before index-date were selected using incidence-density sampling. Exposure of interest was antibiotic therapy >1year before index-date. Adjusted odds-ratios (AORs) and 95% confidence intervals (CIs) were estimated for each antibiotic type using conditional logistic regression.
125,441 cases and 490,510 matched controls were analysed. For gastro-intestinal malignancies, the use of penicillin was associated with an elevated risk of oesophageal, gastric and pancreatic cancers. The association increased with the number of antibiotic courses and reached 1.4 for gastric cancers associated with >5 courses of penicillin (95% CI 1.2-1.8). Lung cancer risk increased with the use of penicillin, cephalosporins, or macrolides (AOR for >5 courses of penicillin: 1.4 95% CI 1.3-1.6). The risk of prostate cancer increased modestly with the use of penicillin, quinolones, sulphonamides and tetracyclines. The risk of breast cancer was modestly associated with exposure to sulphonamides. There was no association between the use of anti-virals and anti-fungals and cancer risk.
Recurrent exposure to certain antibiotics may be associated with cancer risk in specific organ sites.
Copyright © 2015 Elsevier Ltd. All rights reserved.
Brexpiprazole (Rexulti(®)) is an atypical antipsychotic that has been developed by Otsuka Pharmaceutical Co. Ltd and H. Lundbeck A/S as an oral treatment for several psychiatric disorders. Brexpiprazole is a novel serotonin-dopamine activity modulator that acts as a partial agonist of serotonin 1A (5-HT1A) and dopamine D2 receptors, as well as a potent antagonist of 5-HT2A receptors and noradrenergic α1B and α2C receptors. In July 2015, brexpiprazole received its first approval in the USA for use as an adjunctive treatment of major depressive disorder (MDD) and the treatment of schizophrenia. In several countries, brexpiprazole is in development for MDDs, schizophrenia, post-traumatic stress disorder and agitation in patients with dementia of the Alzheimer's type. This article summarizes the milestones in the development of brexpiprazole leading to its first global approval in MDD and schizophrenia.
An HIV-1 DNA prime vaccine, with a recombinant adenovirus type 5 (rAd5) boost, failed to protect from HIV-1 acquisition. We
studied the nature of the vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1–reactive plasma Ab titers
were higher to Env gp41 than to gp120, and repertoire analysis demonstrated that 93% of HIV-1–reactive Abs from memory B cells
responded to Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies were non-neutralizing and frequently polyreactive
with host and environmental antigens, including intestinal microbiota (IM). Next-generation sequencing of an immunoglobulin
heavy chain variable region repertoire before vaccination revealed an Env-IM cross-reactive Ab that was clonally related to
a subsequent vaccine-induced gp41-reactive Ab. Thus, HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing
gp41-reactive Ab repertoire response that was associated with no vaccine efficacy.
Significance
Commensal microbes affect autoimmunity, but it is not clear how. Type 1 diabetes is an organ-specific autoimmune disorder, and it too can be influenced by commensal microbiota. However, the complexity of the microbiota makes it difficult to connect specific microbes with disease progression or prevention. Studies of signaling pathways that microbes stimulate may shed light on disease pathogenesis and provide tools to interfere with it. We found that different Toll-like receptors can induce both pro- and antidiabetogenic signals. Both signals are triggered by commensal microbes, but the former signals control the microbiota, whereas the latter induce tolerance to self-antigens. Identification of signaling pathways that link commensal microbes with autoimmunity shortens the path to intervention with autoimmunity.
The mucosal barrier plays an integral function in human health as it is the primary defense against pathogens, and provides a critical transition between the external environment and the human internal body. In the context of HIV infection, the most relevant mucosal surfaces include those of the gastrointestinal (GI) and genital tract compartments. Several components help maintain the effectiveness of this mucosal surface, including the physical anatomy of the barrier, cellular immunity, soluble factors, and interactions between the epithelial barrier and the local microenvironment, including mucus and host microbiota. Any defects in barrier integrity or function can rapidly lead to an increase in acquisition risk, or with established infection may result in increased pathogenesis, morbidities, or mortality. Indeed, a key feature to all aspects of HIV infection from transmission to pathogenesis is disruption and/or dysfunction of mucosal barriers. Herein, we will detail the host-pathogen relationship of HIV and mucosal barriers in both of these scenarios.
Copyright © 2015. Published by Elsevier Ltd.
Evidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests that Fusobacterium nucleatum may promote colonic neoplasia development by downregulating antitumor T cell-mediated adaptive immunity.
To test the hypothesis that a greater amount of F nucleatum in colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue.
A cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses' Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount of F nucleatum in colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount of F nucleatum with densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutation status. We adjusted the 2-sided α level to .013 for multiple hypothesis testing.
Densities of CD3+, CD8+, CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])+, and FOXP3+ T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis.
F nucleatum was detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared with F nucleatum-negative cases, F nucleatum-high cases were inversely associated with the density of CD3+ T cells (for a unit increase in quartile categories of CD3+ T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87]; P for trend = .006). The amount of F nucleatum was not significantly associated with the density of CD8+, CD45RO+, or FOXP3+ T cells (P fortrend = .24, .88, and .014, respectively).
The amount of tissue F nucleatum is inversely associated with CD3+ T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis.
The three common themes that underlie the induction and perpetuation of autoimmunity are genetic predisposition, environmental factors, and immune regulation. Environmental factors have gained much attention for their role in triggering autoimmunity, with increasing evidence of their influence as demonstrated by epidemiological studies, laboratory research, and animal studies. Environmental factors known to trigger and perpetuate autoimmunity include infections, gut microbiota, as well as physical and environmental agents. To address these issues, we will review major potential mechanisms that underlie autoimmunity including molecular mimicry, epitope spreading, bystander activation, polyclonal activation of B and T cells, infections, and autoinflammatory activation of innate immunity. The association of the gut microbiota on autoimmunity will be particularly highlighted by their interaction with pharmaceutical agents that may lead to organ-specific autoimmunity. Nonetheless, and we will emphasize this point, the precise mechanism of environmental influence on disease pathogenesis remains elusive.
This review will highlight recent advances functionally linking the gut microbiome with mucosal and systemic immune cell activation underlying autoimmunity.
Dynamic interactions between the gut microbiome and environmental cues (including diet and medicines) shape the effector potential of the microbial organ. Key bacteria and viruses have emerged that, in defined microenvironments, play a critical role in regulating effector lymphocyte functions. The coordinated interactions between these different microbial kingdoms - including bacteria, helminths, and viruses (termed transkingdom interactions) - play a key role in shaping immunity. Emerging strategies to identify immunologically relevant microbes with the potential to regulate immune cell functions both at mucosal sites and systemically will likely define diagnostic and therapeutic targets.
The microbiome constitutes a critical microbial organ with coordinated interactions that shape host immunity.
Given the recognized role of the commensal microbiota in regulating host immunity to pathogens, it is not surprising that microbiota are also capable of regulating autoimmune responses. The underlying mechanisms of autoimmune regulation by the microbiota are just beginning to emerge. Here, we discuss possible pressure points toward the development of autoimmune diseases that can be influenced by the microbiota. Besides acting on the adaptive and innate arms of the immune response, the microbiota can affect the targets of autoimmunity directly, even during development in utero, and be involved in regulation of autoimmunity via interactions with hormones.
Copyright © 2015 Elsevier Inc. All rights reserved.
Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.
Copyright © 2015 Elsevier Inc. All rights reserved.
A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications.
Copyright © 2015, American Association for the Advancement of Science.
Bacteria, such as Fusobacterium nucleatum, are present in the tumor microenvironment. However, the immunological consequences of intra-tumoral bacteria remain unclear. Here, we have shown that natural killer (NK) cell killing of various tumors is inhibited in the presence of various F. nucleatum strains. Our data support that this F. nucleatum-mediated inhibition is mediated by human, but not by mouse TIGIT, an inhibitory receptor present on all human NK cells and on various T cells. Using a library of F. nucleatum mutants, we found that the Fap2 protein of F. nucleatum directly interacted with TIGIT, leading to the inhibition of NK cell cytotoxicity. We have further demonstrated that tumor-infiltrating lymphocytes expressed TIGIT and that T cell activities were also inhibited by F. nucleatum via Fap2. Our results identify a bacterium-dependent, tumor-immune evasion mechanism in which tumors exploit the Fap2 protein of F. nucleatum to inhibit immune cell activity via TIGIT.
Copyright © 2015 Elsevier Inc. All rights reserved.