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IL23R signaling in Treg cells suppresses anti-tumor immunity (a-f) Il23rfl/fl and Foxp3Cre-YFPIl23rfl/fl mice were inoculated s.c. with MC38 tumor cells (a-c) or inoculated s.c. with YUMMER1.7 tumor cells (d-f) and tumor-infiltrating T cells were analyzed by flow cytometry on day 24 (a-c) or 14 (d-f) post-inoculation. TILs from MC38 tumors were re-stimulated with PMA/Ionomycin prior flow cytometry analysis. Data display 2 independent experiments with n = 6-10. (a, d) UMAP with overlaid FlowSOM clustering (left) (gated on CD45⁺ TCRβ⁺ and TCRγδ⁺ cells) and heatmap depicting relative marker expression among identified cell clusters (right). (b, e) Violin plots depicting cell numbers of identified T cell clusters per gram tumor. Data are displayed as mean +/- SEM. Statistical significance was determined using two-tailed Mann-Whitney U-tests. (c, f) Dotplots displaying median marker expression in identified T cell clusters comparing Foxp3Cre-YFP Il23Rfl/fl and Il23Rfl/fl mice. Color represents log(median expression Foxp3Cre-YFP Il23Rfl/fl / median expression Il23Rfl/fl); that is red means that median expression is decreased in Foxp3Cre-YFP Il23Rfl/fl in comparison to Il23Rfl/fl mice; green means that median expression is increased in Foxp3Cre-YFP Il23Rfl/fl mice in comparison to Il23Rfl/fl mice. Circle size represent log(p value). Statistically significant changes (p < 0.05) are highlighted with black lines around the circles. Statistical significance was determined using t-tests. (g) C57Bl/6 mice were s.c. inoculated with MC38 tumor cells and tumor-infiltraring T cells were analyzed by flow cytometry on day 14 post-inoculation. Dotplot displaying median marker expression of CD4⁺T cell and Treg cell clusters comparing anti-p19 and isotype antibody treated mice. Color represents log(median expression anti-p19/median expression isotype). Circle size represent log(p value). Statistically significant changes (p < 0.05) are highlighted with black lines around the circles. Data display one out of 2 independent experiments with n = 4-7. Statistical significance was determined using t-tests. Source data
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Interleukin-23 (IL-23) is a proinflammatory cytokine mainly produced by myeloid cells that promotes tumor growth in various preclinical cancer models and correlates with adverse outcomes. However, as to how IL-23 fuels tumor growth is unclear. Here, we found tumor-associated macrophages to be the main source of IL-23 in mouse and human tumor microe...
Citations
... In numerous preclinical trials, the intentional introduction of IL-23 was able to trigger immune resistance against a wide range of tumors [22][23][24][25]. In addition, IL-23 positively regulates those cells located at the junction of innate and adaptive immunity, plays an important role in regulating the stability of the immune system [26,27]. IL-23 is a potent immune-stimulating factor and is part of the IL-12 family, sharing the common subunit p40 with IL-12, which is a potential application for clinical research. ...
A next-generation STING agonist MSA-2 is a promising tumor immunotherapy strategy. However, the methods for improving the anti-tumor efficacy of MSA-2 are a lot of effort. We have demonstrated antitumor effect of platinum-modified MSA-2 (MSA-2-Pt) was better than MSA-2. Here, we combined lipid nanoparticles delivering circular IL-23 mRNA (LNP@cIL-23) and MSA-2-Pt strategy, which showed good antitumor efficacy. Firstly, we synthesized a new series of ionizable phospholipids and formulated and optimized an LNP36 for delivering circular IL-23 mRNA. Then, the combination of LNP36@cIL-23 mRNA and MSA-2-Pt induced tumor cell death and immune activation in the tumor with a single i.t. injection. Finally, the combination of LNP36@cIL-23 mRNA and MSA-2-Pt significantly decreased the melanoma B16F10 tumor and prolonged the survival, demonstrating significant anti-tumor effects. This finding provides promising new avenues for STING activation strategies in tumor immunotherapy.
... As IL17F also plays a role in the inflammation of PsA, IL17is that block both IL17A and IL17F may have a higher efficacy in preventing PsA in patients with PsO [40]. Additionally, recent research studies have identified that IL23 stabilizes regulatory T cells (Treg) in the tumor microenvironment [41,42]. It could be hypothesized that patients with PsO treated with IL23is have more functional Treg cells that alleviate PsA inflammation and therefore have a lower incidence of PsA. ...
Psoriatic arthritis (PsA) is a common comorbidity in patients with psoriasis (PsO) that leads to significant disease burden. Biologic therapies targeting the interleukin (IL)-23/IL-17 axis have been widely used for PsO, but their comparative effectiveness in preventing PsA remains unclear.
The study objective was to compare the occurrence of developing incidental PsA among PsO patients treated with interleukin-23 inhibitors (IL23is) or interleukin-17 inhibitors (IL17is).
A retrospective cohort study was conducted using real-world data from the TriNetX US Collaborative Network, including 53 healthcare organizations. Adult PsO patients treated with IL23is or IL17is between January 2019 and June 2022 were identified. Cox regression analysis was used to assess the risk of PsA incidence, with hazard ratios (HRs) and 95% confidence intervals (CIs) reported. Subgroup analyses were performed based on age, sex, and ethnicity. Sensitivity analyses included comparisons with tumor necrosis factor (TNF) inhibitors (TNFis) to ensure robustness.
A total of 4,580 PsO patients were included in the study, with 2,273 receiving IL23is and 2,307 receiving IL17is. Treatment with IL23is was associated with a significantly lower incidence of PsA compared to IL17is (HR = 0.60, 95% CI 0.44–0.82, P = 0.001). This reduction in risk was particularly notable in the 41- to 65-year age group (HR = 0.42, 95% CI 0.27–0.64, P < 0.001) and among females (HR = 0.57, 95% CI 0.38–0.86, P = 0.007). Subgroup analyses based on ethnicity revealed varying outcomes, with White patients showing a significant risk reduction (HR = 0.55, 95% CI 0.38–0.79, P = 0.001) but no significant risk reduction was observed in Black or African American patients (HR = 1.37, 95% CI 0.37–5.13, P = 0.637). Sensitivity analyses comparing IL23is and TNFis confirmed the robustness of the findings.
IL23is are associated with a lower risk of PsA incidence compared to IL17is in PsO patients, particularly in specific age, sex, and ethnic groups. These findings suggest that IL23is may be more suitable for PsO patients at high risk of PsA and could inform potential updates to treatment guidelines. Further research should focus on refining therapeutic strategies by incorporating patient-specific factors such as comorbidities, ethnicity, and genetic predispositions, which could optimize biologic selection and enhance PsA prevention efforts in clinical practice.
... Preclinical models of solid cancer in combination with genetic ablation of IL-23R in Treg cells have demonstrated that this particular cell type plays an essential role in mediating the tumor-promoting effects of IL-23. IL-23 represents a critical signal that drives the maintenance and stabilization of effector Treg cells by engaging with the transcription factor Foxp3 [126]. Conversely, in certain settings, IL-23R activation may enhance immune responses against tumors by promoting immune cell recruitment and activation [9]. ...
IL-23R (interleukin-23 receptor), found on the surface of several immune cells, plays a key role in the immune system. Indeed, this process is not limited to the inflammatory response but also plays a role in the adaptive immune response. The binding between IL-23R and its specific ligand, the interleukin 23, initiates a number of specific signals by modulating both properties and behavior of immune cells. In particular, it is critical for the regulation of T helper 17 cells (Th17). Th17s are a subset of T cells involved in autoimmune and inflammatory diseases, as well as in cancer. The clinical relevance of IL-23R is underscored by its association with an elevated susceptibility or diminished vulnerability to a spectrum of diseases, including psoriasis, ankylosing spondylitis, and inflammatory bowel disease (IBD). Evidence has emerged that suggests it may also serve to predict both tumor progression and therapeutic responsiveness. It is noteworthy that the IL-23/IL-23R pathway is emerging as a promising therapeutic target. A number of biologic drugs, such as monoclonal antibodies, are currently developing with the aim of blocking this interaction, thus reducing inflammation. This represents a significant advancement in the field of medicine, offering new hope for pursuing more effective and personalized treatments. Recent studies have also investigated the role of such a pathway in autoimmune diseases, and its potential impact on infections as well as in carcinogenesis. The aim of this review is to focus on the role of IL-23R in immune genetics and its potential for modulating the natural history of neoplastic disease.
... After re-clustering of the Treg clusters, four subclusters were identified (Figs. S5A-C and 6A): progenitor-like Tregs (Prog_like), activated Tregs (activatedTreg), eTregs, and Tregs expressing interferon-stimulated genes (TregISG), as in previous reports [32]. The proportion of each cluster did not change significantly in the HIGH group compared with the MID group (Fig. 6B). ...
... As with CD8 + TILs, IFNG responsiveness was reduced in the HIGH group compared with the MID group, and the HIGH group had a lower Treg suppression score, but a high memory score (Fig. 6C-D). As in previous reports [32], CTLA4 expression was highest in eTregs (Fig. S5D). CD44 expression was low in the HIGH group, but CTLA4 showed high expression, similar to the MID group (Fig. 6E-F). ...
Background
Gastric cancer (GC) shows limited response to immune checkpoint inhibitors due to its complex tumor immune microenvironment (TIME). This study explores the functions of various immune cells in the complex TIME in GC.
Methods
We assessed CD8 + T-cell infiltration of GC tissues by immunohistochemistry, and performed single-cell RNA sequencing (scRNA-seq) of tumor and normal tissues from 34 patients with GC.
Results
We categorized 157 GC patients into LOW, MID, and HIGH groups based on their CD8 + T-cell infiltration. Overall survival was notably lower for the HIGH and LOW groups compared with the MID group. Our scRNA-seq data analysis showed that CD8 + T-cell activity markers in the HIGH group were expressed at lower levels than in normal tissue, but the T-cell-attracting chemokine CCL5 was expressed at a higher level. Notably, CD8 + T-cells in the HIGH group displayed lower PD1 expression and higher CTLA4 expression. TCR repertoire analysis using only Epstein–Barr virus-negative cases showed that CD8 + T-cell receptor clonality was lower in the HIGH group than in the MID group. Furthermore, in the HIGH group, the antigen-presenting capacity of type 1 conventional dendritic cells was lower, the immunosuppressive capacity of myeloid-derived suppressor cells was higher, and the expression of CTLA4 in regulatory T-cells was higher.
Conclusion
The present data suggest that the infiltration of inactive CD8 + T-cells with low clonality is induced by chemotaxis in the HIGH group, possibly leading to a poor prognosis for patients with GC.
... Recent research has highlighted the prognostic significance of Treg cells across different cancer types. The predominance of Treg cells is linked not just to adverse outcomes in a range of tumors but also to the creation of an immunosuppressive tumor microenvironment [38,39]. Increased presence of Treg cells in tumor sites is associated with poorer prognosis in cancer patients [40,41]. ...
Background
Regulatory T cells (Tregs) play a critical role in shaping the immunosuppressive microenvironment within tumors. Investigating the role of Tregs in Clear cell renal cell carcinoma (ccRCC) is crucial for identifying prognostic markers and therapeutic targets for ccRCC.
Methods
Weighted gene co-expression network analysis (WGCNA) was utilized to pinpoint modules related to Treg infiltration in TCGA-KIRC samples. Following this, consensus clustering was employed to derive two clusters associated with Treg infiltration in ccRCC. A prognostic model was then developed using the gene module associated with Treg infiltration. We then evaluated the ability of the prognostic model to predict ccRCC overall survival and demonstrated that RCN1 can be used as a target to predict ccRCC prognosis.
Results
We deduce that the two clusters associated with Treg infiltration exhibit distinct compositions of the immune microenvironment, pathway activations, prognosis, and drug sensitivities commonly utilized in ccRCC treatment. Furthermore, a 7-gene model risk score, developed based on ccRCC Treg infiltration, proved to be a reliable prognostic marker in both training and validation cohorts. Additionally, survival analysis indicated that RCN1 serves as a reliable prognostic factor for ccRCC. Single-cell sequencing analysis revealed that RCN1 is predominantly expressed in tumor cells. A pan-cancer analysis highlighted that RCN1 is linked with poor prognosis and the activation of inflammatory response pathways across various cancers.
Conclusion
We developed a prognostic model associated with Treg infiltration, which facilitates the clinical categorization of ccRCC progression. Moreover, our findings underscore the significant potential of RCN1 as a ccRCC biomarker.
... Tumor-associated macrophages, the primary source of IL-23 in the tumor microenvironment, have been linked to the immunosuppressive properties of IL-23. A recent study revealed that a subset of tumor-infiltrating regulatory T (Treg) cells exhibits a suppressive phenotype mediated through Il23r, suggesting that reducing IL-23 could diminish its tumor-promoting effects by stabilizing an effector cell program [82]. ...
Background
Immune stressors, such as lipopolysaccharides (LPS), profoundly affect microbiota balance, leading to gut dysbiosis. This imbalance disrupts the metabolic phenotype and structural integrity of the gut, increasing intestinal permeability. During puberty, a critical surge in estrogen levels is crucial for mammary gland development. However, inflammation originating from the gut in this period may interfere with this development, potentially heightening breast cancer risk later. The long‐term effects of pubertal inflammation on mammary development and breast cancer risk are underexplored. Such episodes can dysregulate cytokine levels and microRNA expression, altering mammary cell gene expression, and predisposing them to tumorigenesis.
Methods
This study hypothesizes that prebiotics, specifically Lentinula edodes Cultured Extract (AHCC), can counteract LPS's adverse effects. Using BALB/c mice, an acute LPS dose was administered at puberty, and breast cancer predisposition was assessed at 13 weeks. Cytokine and tumor‐related microRNA levels, tumor development, and cancer stem cells were explored through immunoassays and qRT‐PCR.
Results
Results show that LPS induces lasting effects on cytokine and microRNA expression in mammary glands and tumors. AHCC modulates cytokine expression, including IL‐1β, IL‐17A/F, and IL‐23, and mitigates LPS‐induced IL‐6 in mammary glands. It also regulates microRNA expression linked to tumor progression and suppression, particularly counteracting the upregulation of oncogenic miR‐21, miR‐92, and miR‐155. Although AHCC slightly alters some tumor‐suppressive microRNAs, these changes are modest, highlighting a complex regulatory role that warrants further study.
Conclusion
These findings underscore the potential of dietary interventions like AHCC to mitigate pubertal LPS‐induced inflammation on mammary gland development and tumor formation, suggesting a preventive strategy against breast cancer.
... 39 In a recent research, Tobias Wertheimer et al found tumorassociated macrophages to be the main source of IL-23 in mouse and human tumor microenvironments. 40 Consistent with previous studies, in this work, we found that IL-23, as a severe-irAEs-associated gene, was mainly transcribed by monocytes in human peripheral blood based on scRNA-seq analysis. ...
Background
Immune-related adverse events (irAEs), characterized by targeted inflammation, occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). Evidence proved that the baseline peripheral blood profiles of patients at risk for severe irAEs development paralleled clinical autoimmunity. Interleukin (IL)-23 blockade with risankizumab is recommended for cases that are suffering from autoimmune disease, such as autoimmune colitis. However, currently, the role of IL-23 in irAEs onset and severity remains poorly understood.
Methods
The pro-inflammatory cytokines most associated with severe irAEs onset were identified by retrospective analysis based on GSE186143 data set. To investigate the efficacy of prophylactic IL-23 blockade administration to prevent irAEs, refer to a previous study, we constructed two irAEs murine models, including dextran sulfate sodium salt (DSS)-induced colitis murine model and a combined-ICIs-induced irAEs murine model. To further explore the applicability of our findings, murine models with graft-versus-host disease were established, in which Rag2−/−Il2rg−/− mice were transferred with human peripheral blood mononuclear cells and received combined cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) treatment. Human melanoma cells were xenografted into these mice concomitantly.
Results
Here we show that IL-23 was upregulated in the serum of patients suffering from irAEs after dual anti-CTLA-4 and anti-PD-1 treatment, and increased as a function of irAEs severity. Additionally, Augmented CD4⁺ Tems may preferentially underlie irAEs onset. Treating mice with anti-mouse IL-23 antibody concomitantly with combined CTLA-4 and PD-1 immunotherapy ameliorates colitis and, in addition, preserves antitumor efficacy. Moreover, in xenografted murine models with irAEs, prophylactic blockade of human IL-23 using clinically available IL-23 inhibitor (risankizumab) ameliorated colitis, hepatitis and lung inflammation, and moreover, immunotherapeutic control of tumors was retained. Finally, we also provided a novel machine learning-based computational framework based on two blood-based features—IL-23 and CD4⁺ Tems—that may have predictive potential for severe irAEs and ICIs response.
Conclusions
Our study not only provides clinically feasible strategies to dissociate efficacy and toxicity in the use of combined ICIs for cancer immunotherapy, but also develops a blood-based biomarker that makes it possible to achieve a straightforward and non-invasive, detection assay for early prediction of irAEs onset.
... No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications 69,70 . Data distribution was assumed to be normal, but this was not formally tested. ...
Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8⁺ T cell response, and triggers macrophage ‘nutritional immunity’ to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into ‘oncobiotics’ for a multi-layered approach to cancer therapy.
Background/Objectives: Immunosenescence implies innate and adaptive immunity dysfunction, which naturally occurs with aging. It is a complex multifactorial process which can be triggered by either genetic changes, immune changes or both. Numerous research studies have shown that the process of senescence goes alongside chronic immune activation. The purpose of this study is to analyze the changes in the expression of genes associated with adaptive and innate immune responses in order to identify reliable biomarkers for immune aging. Methods: For that aim, 55 clinically healthy individuals of active age (21–65 years) were distributed based on immunophenotyping in two groups, with and without signs of premature senescence. A gene expression analysis was subsequently made on those two groups, and the differentially expressed genes were presented and interpreted. Results: Altogether, forty-eight (48) genes exhibited differential expression between the two groups, most of which showed up-regulation (45) (fold change more than 2), and only three were down-regulated (fold change less than −2). The highest positive fold change showed IL-1β (10.76), BCL6 (13.25) and CCL4 (15.91), while the highest negative fold changes were documented for IL23R (−3.10), IL5 (−2.66) and PTGS2 (COX-2) (−2.15). Conclusions: Our results reveal that immunosenescence is positively associated with chronic inflammation, which is typical for the aging process. On the other hand, we identified markers of possible protective effects against oxidative stress and tumorigenesis. These findings can aid the early diagnosis of chronic degenerative diseases in subclinical phase, as well as the development of strategies to prevent the processes of premature immune aging.
