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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 [shEZH2]
| PRJNA292385 | ENA
Project description:Epigenetic silencing of Th1 chemokines shapes tumor immunity, immunotherapy and patient outcome [GSK126]
| PRJNA292384 | ENA
Project description:Glioblastoma is an aggressive brain malignancy with a dismal prognosis. With emerging evidence that disproves the immune privileged environment in the brain, there is much interest in examining various immunotherapy strategies to treat these incurable cancers. Unfortunately, to date, clinical studies investigating immunotherapy regimens have not provided much evidence of efficacy, leading to questions about the suitability of immunotherapy strategies for these tumors. Inadequate inherent populations of lymphocytes in tumor (TILs) and limited trafficking of systemic circulating T cells into the central nervous system (CNS) likely contribute to the poor response to immunotherapy treatment for primary CNS cancers. This paucity of TILs is in concert with the finding of epigenetic silencing of genes that promote immune cell movement (chemotaxis) to the tumor. In this study we evaluated the ability of GSK126, a blood-brain barrier permeable small molecule inhibitor of EZH2, to reverse the epigenetic silencing of chemokines like CXCL9 and CXCL10. When combined with anti-PD-1 treatment, these IFN driven chemokines promote T cell infiltration, resulting in decreased tumor growth and enhanced survival in immunocompetent murine sub-cutaneous and intracranial tumor syngeneic models of GBM. Examination of the tumor micro-environment revealed that the decrease in tumor growth in the mice treated with the drug combination was accompanied by increased tumor CD8 T cell infiltration along with higher IFN expression. Additionally, a significant increase in CXCR3+ T cells in the draining lymph nodes was also found. Taken together, our data suggests that in glioblastoma, epigenetic modulation using GSK126 could improve current immunotherapy strategies by reversing the epigenetic changes that enable immune cell evasion leading to enhanced immune cell trafficking to the tumor.
2021-06-11 | ST001838 | MetabolomicsWorkbench
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: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: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: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: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
Project description:Targeting the RNA m6A reader YTHDF2 in tumor-associated macrophages shapes tumor immunity and immunotherapy
| PRJNA778729 | ENA
Project description:Tumor-induced immunosuppression remains a major challenge for immunotherapy of cancer patients. To further elucidate why an allogeneic gene-modified (Interleukin-7(IL-7)/CD80 co-transfected) renal cell cancer vaccine failed to induce clinically relevant TH1-polarized immune responses, peripheral blood mononuclear cells (PBMCs) from enrolled study patients were analyzed by gene expression profiling (GEP) both prior and after vaccination. At baseline before vaccination, a profound downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines and signaling/transcription factors was observed in renal cell cancer patients as compared to healthy controls. Vaccination led to a partial reversion of preexisting immunosuppression, however, GEP indicated that an appropriate TH1 polarization could not be achieved. Most interestingly, our results suggest that the nuclear factor kappa B (NF-M-NM-:B) signaling pathway might be involved in the impairment of immunological responsiveness and the observed TH2 deviation. In summary, our data suggest that GEP might be a powerful tool for the prediction of immunosuppression and the monitoring of immune responses within immunotherapy trials. Gene expression was profiled using Affymetrix Human Gene v1.1 ST microarrays in the following settings: 9 RCC patients were profiled before and after vaccination (pairs of measurements) and additionally 9 healthy control samples were profiled.
2014-09-24 | E-GEOD-51490 | biostudies-arrayexpress