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Role of CD4⁺ T cells and cDC1 cells in NK cell recruitment to tumours a, Effect of CD4⁺ T cells on migratory DC populations in the tdLNs of mice immunized with MICB-vax versus Ctrl-vax. Total migratory DCs as well as cDC1 and cDC2 cells were quantified 2 d after induction of MICB expression in tumour cells by doxycycline treatment (n = 7 mice per group, except n = 6 for Ctrl-vax without anti-CD4). b, Migratory DC subsets within the tdLN of MICB-vax-immunized mice treated following immunization (days 28 + 30) with isotype-control, CD4-depleting or CD40L-blocking monoclonal antibody (n = 7 mice per group). c, Quantification of DC populations within the tumours of mice immunized with Ctrl-vax (blue) or MICB-vax (red) on day 7 following induction of MICB expression with doxycycline (n = 7 mice per group). d, Effect of cDC1 depletion on MICB vaccine-induced T cell and NK cell accumulation within tumours in Xcr1DTR mice. Mice were treated with DT or left untreated starting on day 26 following immunization with Ctrl-vax or MICB-vax (days 0 + 14) and B16F10 (MICB-dox) tumour implantation (day 21). Immune cells were analysed in tumours 7 d after induction of MICB expression on tumours with doxycycline (day 37) (n = 7 mice per group). e, Contribution of vaccine-induced anti-MICB antibodies to DC-mediated cross-presentation of tumour antigens to CD8⁺ T cells. Bone marrow-derived DCs (BMDCs) were pre-incubated with B2m-knockout B16F10 (MICB-OVA) tumour cells in the presence of affinity-purified serum IgG from mice immunized with Ctrl-vax or MICB-vax at the indicated concentrations. DCs were co-cultured with CFSE-labelled OT-1 CD8⁺ T cells with T cell proliferation as the readout. The role of activating Fc receptor (FcR) was assessed using BMDCs from Fcer1g–/– mice (orange) or pre-incubation of BMDCs with FcR-blocking antibody (yellow) before tumour cell addition. Representative data from two independent experiments are shown in a–e. Statistical significance was assessed by one-way ANOVA with Tukey’s multiple-comparison test (a, b, d), two-tailed Mann–Whitney test (c) and two-way ANOVA with Tukey’s multiple-comparison test (e). Data are depicted as the mean ± s.e.m. (a–d) or mean ± s.d. (e). Source data
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Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation1. Here we report a...
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Citations
... A significant advancement in this field emerged with the development of a cancer vaccine targeting MICA and MICB (MICA/B). This innovative approach induces a coordinated attack by both T cell and NK cell populations, maintaining effectiveness against MHC class I-deficient tumors through the combined action of NK cells and CD4+ T cells (160). ...
Neoantigen-based cancer vaccine therapy represents a promising precision oncology strategy that targets unique tumor-specific mutations to elicit a robust immune response. This therapeutic approach is designed to harness the host’s immune response against tumor-specific neoantigens to eliminate cancer cells. The efficacy of neoantigen vaccines dependents on the coordinated action of diverse immune cells, including T lymphocytes, dendritic cells, B lymphocytes, natural killer cells, and macrophages. Each cell type plays a distinct and crucial role in recognizing, targeting, and destroying malignant cells. Understanding the mechanisms governing both individual and collective immune cell dynamics is crucial for therapeutic success. This comprehensive review systematically explores the mechanisms of neoantigen-specific immune cells, their dynamic interactions, and clinical application progress, aiming to unveil their potential value and future development in cancer treatment.
... This innovative vaccine demonstrated potential for developing therapies that combine multiple immune effects to combat cancer. [71] Moreover, FTn is organized in octahedral symmetry with eight threefold axes on its surface, making it well-suited for presenting viral proteins. Leveraging this property, Nabel's group employed the structural knowledge of FTn to design selfassembled nanoparticles capable of eliciting more potent immune responses than traditional flu vaccines. ...
Nanomedicines have demonstrated significant potential in disease diagnosis and therapy, revolutionizing traditional drug development patterns. Recently, inspired by both natural and engineering principles, synthetic biology integrates the complexity of biological systems with the precision of engineering to design and create novel biological components, devices, and systems. This convergence of synthetic biology and nanomedicine has led to the emergence of a new concept: synthetic biological nanomedicine. Unlike traditional or biomimetic nanomedicines, synthetic biological nanomedicines are designed using gene engineering‐based strategies. In this Perspective, the foundational concepts of synthetic biological nanomedicine are introduced and its relationship to, and differences from, traditional and biomimetic nanomedicine are explored. Drawing from synthetic biology, synthetic biological nanomedicine also incorporates two main approaches: top‐down and bottom‐up strategies. The latest advancements in the application of synthetic biology to nanomedicine are reviewed, these developments are categorized according to the aforementioned strategies, and a discussion of the potential advantages and challenges associated with utilizing synthetic biology in nanomedicine development is concluded.
... Among patients in high-risk group, reduced immune infiltration suggests potential benefits from combination immunotherapies, such as PD-1/PD-L1 inhibitors, targeted suppression of inhibitory cytokines, cancer vaccines, or autologous immune cell infusions, may enhance antitumor efficacy (50). Recent advancements have also led to the development of cancer vaccines capable of inducing dual antitumor responses from T cells and NK cells (51). Therefore, the CBRD risk score system may provide potential predictive value for combination immunotherapy strategies, particularly for high-risk breast cancer patients with diminished immune infiltration. ...
Introduction
Breast cancer is among the most prevalent malignant tumors globally, with carboplatin serving as a standard treatment option. However, resistance often compromises its efficacy. DNA damage repair (DDR) pathways are crucial in determining responses to treatment and are also associated with immune infiltration. This study aimed to identify the DDR genes involved in carboplatin resistance and to elucidate their effects on prognosis, immune infiltration, and drug sensitivity in breast cancer patients.
Methods
A 3D-culture model resistant to carboplatin was constructed and sequenced. Co-expressed DDR genes were analyzed to develop a predictive model. Immune infiltration analysis tools were employed to assess the immune microenvironment of patients with varying expression levels of these risk genes. Additionally, drug sensitivity predictions were made to evaluate the efficacy of other DNA damage-related drugs across different risk groups. Molecular assays were performed to investigate the role of the key gene TONSL in breast cancer.
Results
By integrating data from public database, we established a prognostic signature comprising thirteen DDR genes. Our analysis indicated that this model is associated with immune infiltration patterns in breast cancer patients, particularly concerning CD8+ T cells and NK cells. Additionally, it demonstrated a significant correlation with sensitivity to other DDR-related drugs, suggesting its potential as a biomarker for treatment efficacy. Compared to the control group, TONSL-knockdown cell lines exhibited a diminished response to DNA-damaging agents, marked by a notable increase in DNA damage levels and enhanced drug sensitivity. Furthermore, single-cell analysis revealed elevated TONSL expression in dendritic and epithelial cells, particularly in triple-negative breast cancers.
Conclusions
Carboplatin resistance-related DDR genes are associated with prognosis, immune infiltration, and drug sensitivity in breast cancer patients. TONSL may serve as a potential therapeutic target for breast cancer, particularly in triple-negative breast cancer, indicating new treatment strategies for these patients.
... Due to the lack of innate immunity, it is difficult to be recognized and killed by immune cells, and the immune checkpoint inhibitor ICIs are also difficult to play a role [1]. The cause of its immune deficiency may be (1) lack of tumor-related antigens (2) deficiency of antigen-presenting cells APCs (3) deletion of T cell activation (4) damage to the transport of T cells to the tumor [2]. Therefore, how to convert cold tumors into hot tumors is also a research hotspot in tumor treatment. ...
... According to the classification of target sites, tumor vaccines can be divided into tumor-related antigen (TAAs) vaccines and new antigen (TSAs) vaccines. Both of these show significant effects in the activation of T cells and NK cells [4]. Among them, TAAs vaccines have strong immunogenicity, but they need to face autoimmune problems, which may produce some side effects. ...
... Among the above methods, tumor vaccine is a new therapy that is considered to have strong anticancer activity (Figure 2). It mainly realizes the conversion of cold tumors to hot tumors by activating the immune response of T cells and NK cells [4]. Tumor vaccine can expand the number of specific T cells and increase the transportation of T cells to the tumor area [19]. ...
Compared with hot tumors, cold tumors are a more difficult problem at present. Because cold tumors lack in congenital immunity, it is difficult for ordinary immune examination inhibitors to work. Therefore, how to "ignite" cold tumors as hot tumors is the focus of the current research. At present, scholars have proposed different and corresponding methods for various causes of T cell immunodeficiency. Among them, tumor vaccines stand out from the principle of activating the immune response of T cells and NK cells, and is currently generally recognized as a new therapy and research hotspot with strong anti-cancer activity. By classifying the target sites of tumor vaccines, they can be divided into tumor-related antigen (TAAs) vaccines and new antigen (TSAs) vaccines. Both vaccines have shown significant effects in activating T cells and NK cells. In terms of the current development status of the two vaccines, more and more research teams have invested in the research of TSAs vaccines, and many teams still insist on the research of TAAs vaccines. Although these two vaccines have their own difficulties to overcome, they still have made great contributions to the development of tumor treatment research, and both have advantages and broad prospects that cannot be reached by other methods. It is believed that no more effective tumor vaccines have been put into clinical trials.
... These antibodies attach to MICA/B at the point of proteolytic cleavage, hence preventing shedding. In preclinical research, immunisation produced strong anti-tumour responses that were reliant on both NK and T cells [62,63] . Since CLN-619 is the only MICA/B-targeted mAb available in the clinic, Cullinan Oncology is taking a promising approach to targeting suppression of MICA/B shedding. ...
Background: Immunological oncology has transformed cancer therapy, thereby increasing patients' chances of survival and quality of life. Natural killer (NK) cells, specifically, have come to prominence as powerful engines of the inherent immune system response, making them a prospective immunotherapy tool. One of the most crucial NK cell receptors namely NK-group 2, member D (NKG2D) has a pivotal role in both innate and adaptive immunity for establishing the degree of activation of NK cells. It serves as a pertinent activating receptor in the immunological identification and extermination of aberrant cells by natural killer cells and T lymphocytes, recognising a wide variety of ligands to offer comprehensive target specificity. Objective: This article aimed to emphasise a better understanding of the NKG2D receptor's structure, its signalling mechanism, and its potential and prospective implementation in a variety of medical contexts. Method: A search for published material was carried out using some combinations of the terms "cancer", "immunotherapy", "natural killer" and “NKG2D” on PubMed, ScienceDirect, Scopus, and Google Scholar. All citations from the selected papers were examined. Conclusion: In light of the numerous studies conducted, it is deduced that NKG2D-mediated cancer chemotherapy offers an excellent prospect for usage as a type of chemotherapy soon; nevertheless, additional clinical trials are required before it can be employed in clinical settings. It is crucial to identify and comprehend the functions of several transcription factors that control the expression of NKG2D on the cell membrane by binding to its ligands. Furthermore, approaches centred on augmenting NKG2D expression in immune cells and elevating NKG2DL expression in cancer cells may efficiently trigger the antitumor immune response. Keywords: cancer, immunotherapy, natural killer cell, NK group-2 D receptor
... In addition, ferritin has been extensively investigated for the delivery of viral antigens such as influenza and SARS-CoV-2 antigens [27][28][29][30][31][32], and several clinical studies have shown that ferritin has excellent biosafety as an antigen delivery vehicle [33,34]. However, studies on ferritin as a delivery platform for neoantigen peptides in tumor vaccines have been very limited [35][36][37]. Therefore, we expect to develop a ferritin-based tumor vaccine platform for the delivery of neoantigen peptides to enhance antitumor immune responses. ...
Background
Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle.
Results
Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. The genetically engineered self-assembled particles neoantigen-FNs with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly drainage to and continuously accumulate in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8⁺ T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier.
Conclusions
Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently drainage to lymph nodes and induce efficient antitumor immune responses.
Graphical Abstract
... Since the α3 domain is relatively conserved, it can overcome the effects of MICA/B polymorphism (119). Recently, Badrinath et al (123) designed a tumor vaccine targeting the MICA α3 domain, which can induce the body to produce antibodies against the MICA α3 domain, inhibiting the proteolytic shedding of MICA/B from tumor cells, enhancing the cytotoxic function of NK cells, and increasing the cDC1-mediated cross-presentation of tumor antigens to CD8 + T cells, inducing responses against MICA/B in both CD4 + and CD8 + T cells (123). mAbs targeting sNKG2DL neutralize and reduce immunosuppressive effects. ...
... Since the α3 domain is relatively conserved, it can overcome the effects of MICA/B polymorphism (119). Recently, Badrinath et al (123) designed a tumor vaccine targeting the MICA α3 domain, which can induce the body to produce antibodies against the MICA α3 domain, inhibiting the proteolytic shedding of MICA/B from tumor cells, enhancing the cytotoxic function of NK cells, and increasing the cDC1-mediated cross-presentation of tumor antigens to CD8 + T cells, inducing responses against MICA/B in both CD4 + and CD8 + T cells (123). mAbs targeting sNKG2DL neutralize and reduce immunosuppressive effects. ...
The immune system is integral to the surveillance and eradication of tumor cells. Interactions between the natural killer group 2 member D (NKG2D) receptor and its ligands (NKG2DLs) are vital for activating NKG2D receptor‑positive immune cells, such as natural killer cells. This activation enables these cells to identify and destroy tumor cells presenting with NKG2DLs, which is an essential aspect of tumor immunity. However, tumor immune escape is facilitated by soluble NKG2DL (sNKG2DL) shed from the surface of tumor cells. The production of sNKG2DL is predominantly regulated by metalloproteinases [a disintegrin and metalloproteinases (ADAM) and matrix metalloproteinase (MMP) families] and exosomes. sNKG2DL not only diminish immune recognition on the tumor cell surface but also suppress the function of immune cells, such as NK cells, and reduce the expression of the NKG2D receptor. This process promotes immune evasion, progression, and metastasis of tumors. In this review, an in‑depth summary of the mechanisms and factors that influence sNKG2DL production and their contribution to immune suppression within the tumor microenvironment are provided. Furthermore, due to the significant link between sNKG2DLs and tumor progression and metastasis, they have great potential as novel biomarkers. Detectable via liquid biopsies, sNKG2DLs could assess tumor malignancy and prognosis, and act as pivotal targets for immunotherapy. This could lead to the discovery of new drugs or the enhancement of existing treatments. Thus, the application of sNKG2DLs in clinical oncology was explored, offering substantial theoretical support for the development of innovative immunotherapeutic strategies for sNKG2DLs.
... 11,20,21 The novel mAb 7C6 binds to the proteolytic MICA α3 domain, stabilizing surface MICA/B and enhancing NK cell-mediated ADCC. 22,23 We hypothesized that 7C6 would simultaneously blockade of MICA/B shedding and increase ADCC by memory-like NK cells, resulting in enhanced MM cytotoxicity. ...
... In addition, ferritin has been extensively investigated for the delivery of viral antigens such as in uenza and SARS-CoV-2 antigens [27][28][29], and several clinical studies have shown that ferritin has excellent biosafety as an antigen delivery vehicle [30,31]. However, studies on ferritin as a delivery platform for neoantigen peptides in tumor vaccines have been very limited [32][33][34]. Therefore, we expect to develop a ferritin-based tumor vaccine platform for the delivery of neoantigen peptides to enhance antitumor immune responses. ...
Background
Tumor neoantigen peptide-based vaccines, systemic immunotherapies that enhance antitumor immunity by activating and expanding antigen-specific T cells, have achieved remarkable results in the treatment of a variety of solid tumors. However, how to effectively deliver neoantigens to induce robust antitumor immune responses remains a major obstacle.
Results
Here, we developed a safe and effective neoantigen peptide delivery system (neoantigen-ferritin nanoparticles, neoantigen-FNs) that successfully achieved effective lymph node targeting and induced robust antitumor immune responses. Genetically engineered self-assembled particles with a size of 12 nm were obtained by fusing a neoantigen with optimized ferritin, which rapidly migrates to and continuously accumulates in lymph nodes. The neoantigen-FNs vaccine induced a greater quantity and quality of antigen-specific CD8⁺ T cells and resulted in significant growth control of multiple tumors, dramatic inhibition of melanoma metastasis and regression of established tumors. In addition, no obvious toxic side effects were detected in the various models, indicating the high safety of optimized ferritin as a vaccine carrier.
Conclusions
Homogeneous and safe neoantigen-FNs could be a very promising system for neoantigen peptide delivery because of their ability to efficiently migrate to lymph nodes and induce efficient antitumor immune responses.
... In contrast, impedance of MICA/B shedding promotes antitumor responses against AML [27]. Vaccine-induced increase the density of MICA/B proteins on tumor surface enhances the cytotoxic function of NK cell and T cells [28]. ...
Acute myeloid leukemia (AML) remains challenging due to chemotherapeutic drug-resistance (CDR). Aberrant expression B7 family proteins are involved in tumors evasion. We wonder whether B7 family protein alteration in AML CDR further supports tumor escape. Here, we establish AML cytarabine-resistant cell line U937/Ara-C and report on the expression MHC molecule and B7 family member. HLA-ABC was highly expressed similarly on both cell lines. MIC (MHC class I chain related) A/B and B7-H6 was moderately expressed on the surface of U937 and decreased dramatically by U937/Ara-C. In contrast, enhanced expression of B7-H1 and B7-H7 by U937/Ara-C was observed. HLA-DR and other B7 family members including CD80, CD86, B7-DC, B7-H2, B7-H3, B7-H4, and B7-H5 were not detected by both cell lines. Compared co-cultured with U937, peripheral blood mononuclear cells showed a decreased cytotoxicity when incubated with U937/Ara-C, as indicated by decreased levels of granzyme B and perforin production, accompanied with less TNF-α and lactate dehydrogenase secretion. In conclusion, AML CDR further evades the anti-tumor immune response which may through MHC molecule and B7 family members.
