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PROVIDER: PRJNA292380 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [GSK126]
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Project description:Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [shEZH2]
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Project description:The paper describes a model of immunity to melanoma.
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This model is described in the article:
Modeling anti-tumor Th1 and Th2 immunity in the rejection of melanoma
Raluca Eftimie, Jonathan L. Bramson, David J.D. Earn
Journal of Theoretical Biology 265 (2010) 467–480
Abstract:
Recent experiments indicate that CD4+ Th2 cells can reject skin tumors in mice, while CD4+ Th1 cells cannot (Mattes et al., 2003; Zhang et al., 2009). These results are surprising because CD4+ Th1 cells are typically considered to be capable of tumor rejection. We used mathematical models to investigate this unexpected outcome. We found that neither CD4+ Th1 nor CD4+ Th2 cells could eliminate the cancer cells when acting alone, but that tumor elimination could be induced by recruitment of eosinophils by the Th2 cells. These recruited eosinophils had unexpected indirect effects on the decay rate of type 2 cytokines and the rate at which Th2 cells are inactivated through interactions with cancer cells. Strikingly, the presence of eosinophils impacted tumor growth more significantly than the release of tumor-suppressing cytokines such as IFN-g and TNF-a. Our simulations suggest that novel strategies to enhance eosinophil recruitment into skin tumors may improve cancer immunotherapies.
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2024-09-02 | BIOMD0000000768 | BioModels
Project description:Tumor metabolic reprogramming profoundly shapes antitumor immunity, but the mechanisms linking glutamine metabolism to immune evasion in hepatocellular carcinoma (HCC) remain incompletely understood. Here, we identify the glutamine transporter SLC1A5 as a tumor-intrinsic regulator of HCC progression and antitumor immunity. Genetic deletion or pharmacological inhibition of SLC1A5 suppressed tumor growth across autochthonous, orthotopic, and subcutaneous tumor models and enhanced the efficacy of immune checkpoint blockade. Mechanistically, SLC1A5-dependent glutamine metabolism maintained cellular redox homeostasis and mitochondrial integrity, whereas SLC1A5 loss promoted mitochondrial stress and activation of type I interferon signaling, thereby enhancing antitumor CD8+ T-cell responses. Conversely, SLC1A5 overexpression promoted tumor progression and immune suppression. These findings establish SLC1A5-mediated glutamine metabolism as a metabolic mechanism of immune evasion and suggest SLC1A5 as a potential therapeutic target for improving immunotherapy responses in HCC.
2026-08-20 | MTBLS15401 | MetaboLights
Project description:Overcoming immunosuppression in tumor microenvironment (TME) is crucial for the development of novel cancer immunotherapies. In this study, we revealed a previously unrecognized role of IL-16 in shaping anti-tumor immunity. Compared to healthy individuals, cancer patients exhibited impaired production of IL-16, which was associated with inferior patient prognosis. In multiple murine cancer models, IL-16 administration augmented the anti-tumor immune responses and thus restrained tumor growth. Further investigation uncovered that IL-16 potentiated the polarization of T helper 1 (Th1) cells and the production of their effector cytokine IFN-γ. Mechanistically, IL-16 inhibited glutamine catabolism by downregulating the expression of glutaminase (GLS) in CD4+ T cells. The establishment of IL-16-dependent Th1 tumor microenvironment further increased the expression of CXCR3 ligands in tumor-associated macrophages (TAMs), thereby improving the therapeutic effectiveness of immune checkpoint blockade (ICB). In cancer patients who received anti-PD1 therapy, higher levels of IL-16 were correlated with better responsiveness. Finally, we found that the impaired production of histamine by mast cells was a contributing factor to the downregulation of IL-16 in TME. Therefore, IL-16 could potentially be utilized as a therapeutic approach to augment anti-tumor immunity, and improve the outcome of ICB therapy in cancer patients. Collectively, our research provided new insights into the biological function of IL-16, emphasizing its potential clinical significance in cancer immunotherapy.
2025-01-20 | GSE254991 | GEO
Project description:Overcoming immunosuppression in tumor microenvironment (TME) is fundamental to the development of novel cancer immunotherapies. Herein, we revealed an unrecognized role of IL-16 in shaping anti-tumor immunity. Compared with healthy subjects, cancer patients had impaired production of IL-16, which was correlated with inferior patient prognosis. In multiple murine cancer models, IL-16 administration augmented the anti-tumor immune responses and thus restrained tumor growth. Mechanistically, IL-16 potentiated the polarization of T helper 1 (Th1) cells and the production of their effector cytokine IFN-γ, Mechanistically, IL-16 blocked glutamine catabolism by downregulating glutaminase (GLS) expression in CD4+ T cells. The IL-16-established Th1 tumor microenvironment further increased the expression of CXCR3 ligands in tumor-associated macrophages, which improved the therapeutic efficacy of immune checkpoint blockade (ICB). In cancer patients who received anti-PD1 therapy, high IL-16 levels correlated with better responsiveness. Finally, we found that the impaired production of histamine by mast cells was a causative factor for IL-16 downregulation in TME. Thus, IL-16 administration may serve as a potential approach to augment anti-tumor immunity, and also improve the outcome of ICB therapy in cancer patients. Collectively, we provided new insights into the biological function of IL-16 and thus highlighted its potential clinical value in cancer immunotherapy.
2025-01-20 | GSE247579 | GEO
Project description:Tumor metabolic reprogramming has been recognized as a critical determinant in tumor development and cancer immunotherapy. Aberrant choline metabolism is emerging as a defining hallmark of cancer. However, its impact on antitumor immunity remains largely unclear. Carbohydrate responsive element binding protein (ChREBP)-mediated choline deprivation impels tumor-associated macrophages (TAMs) reprogramming and maintains an immunosuppressive tumor microenvironment (TME). Mechanistically, ChREBP interacts with SP1 to increase the expression of immunosuppressive chemokines CCL2 and CXCL1, as well as choline transporter SLC44A1. As such, high expression of CCL2 and CXCL1 expression promotes recruitment of TAMs and MDSCs in the TME. Tumor cells with high SLC44A1 expression compete consuming choline with M1-like TAMs, inhibiting cGAS-STING signaling and promoting the polarization of M1 to M2 macrophages. Clinically, ChREBP-SP1-choline metabolism axis expression is associated with poor clinical outcome in CRC. Inhibiting ChREBP reduces M2-like TAMs and MDSCs to enhance anti-tumor immunity, suggesting ChREBP as a potential immunotherapy target in cancer.
2025-01-01 | GSE278229 | GEO
Project description:Metabolic reprogramming in tumor cells profoundly shapes the tumor microenvironment (TME) and limits the efficacy of immunotherapy in colorectal cancer (CRC). However, how tumor-intrinsic metabolic alterations orchestrate immune remodeling remains poorly understood. Here, we identify phosphoglycerate dehydrogenase (PHGDH), a key enzyme in the serine biosynthesis pathway, as a critical metabolic regulator of antitumor immunity. Pharmacological inhibition and genetic suppression of PHGDH significantly enhanced the therapeutic response to PD-1 blockade in CRC models. Integrated single-cell transcriptomic analyses revealed that PHGDH inhibition reprograms tumor metabolism, leading to reduced α-ketoglutarate (α-KG) levels in the TME and subsequent epigenetic remodeling of tumor-associated macrophages. Mechanistically, α-KG depletion suppresses KDM5B activity, maintains H3K4me3 enrichment at STAT1 target promoters, and activates JAK–STAT1 signaling, thereby promoting macrophage inflammatory polarization with augmented antigen-presenting capacity. These reprogrammed macrophages promote CD8+ T cell infiltration and cytotoxic function, ultimately amplifying antitumor immunity and sensitizing tumors to ICB. Consistently, clinical analyses demonstrate that low PHGDH expression correlates with an immune-active phenotype and improved immunotherapy outcomes. Collectively, our findings uncover a tumor–macrophage metabolic–epigenetic crosstalk that governs immune responsiveness and highlight PHGDH as a promising therapeutic target and candidate biomarker for immunotherapy in CRC.
2026-03-31 | GSE325746 | GEO
Project description:In this project, we transfected MC38 cells with Flag-tagged Mbtps1 or vector control. After that, we performed immunoprecipitation–mass spectrometry analysis to search the interacting proteins of MBTPS1. In our study, We observed that the loss of membrane-bound transcription factor site-1 protease (MBTPS1) in tumor cells enhanced antitumor immunity and potentiated anti-PD-1 therapy. Mechanistic studies revealed that tumor cell-intrinsic MBTPS1 competed with USP13 for binding to STAT1, thereby disrupting USP13-dependent deubiquitination and stabilization of STAT1. MBTPS1 deficiency induced CXCR3+ CD8+ T cell infiltration by upregulating STAT1-transcribed chemokines including CXCL9, CXCL10 and CXCL11. Notably, the regulatory role of MBTPS1 in antitumor immunity operates independently of its classic function in cleaving membrane-bound transcription factors. Collectively, our results provide a theoretical basis for MBTPS1 as a potential immunotherapy target and also as a predictor of immunotherapy efficacy.
2025-04-11 | PXD053978 | Pride
Project description:The immune system can both promote and suppress cancer. Chronic inflammation and proinflammatory cytokines such as interleukin (IL)-1 and IL-6 are considered tumor-promoting. In contrast, the exact nature of protective antitumor immunity remains obscure. In this study, we have quantified locally secreted cytokines during primary immune responses against myeloma and B-cell lymphoma in mice. Strikingly, successful cancer immunosurveillance mediated by tumor-specific CD4+ T cells was consistently associated with elevated local levels of both proinflammatory (IL-1aplha, IL-1beta, and IL-6) and T helper 1 (Th1)-associated cytokines (interferon-alpha, IL-2, IL-12). Cancer eradication was achieved by a collaboration between tumor-specific Th1 cells and tumor-infiltrating, antigen-presenting macrophages. Th1 cells induced secretion of IL-1? and IL-6 by macrophages. Th1-derived interferon-? was shown to render macrophages directly cytotoxic to cancer cells, and to induce macrophages to secrete the angiostatic chemokines CXCL9/MIG and CXCL10/IP-10. Thus, inflammation, when driven by tumor-specific Th1 cells, may prevent rather than promote cancer. Tumoricidal macrophages were isolated from Idiotype-specific TCR-transgenic SCID mice injected with MOPC315-containing Matrigel. Control macrophages were obtained from TCR-transgenic SCID mice injected with Matrigel containing antigen-loss MOPC315.
2011-03-15 | E-GEOD-26912 | biostudies-arrayexpress