Targeting metabolism to improve immunotherapy in GSNOR-deficient colorectal cancer
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ABSTRACT:
PROVIDER: PRJEB74195 | ENA |
REPOSITORIES: ENA
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Project description:Colorectal cancer (CRC) is the third most diagnosed type of cancer and the second leading cause of cancer death worldwide. Despite the increasing knowledge of CRC molecular biology and the development of new targeted therapies, its high heterogeneity hampers the efficacy of current treatments. Thus, there is a pressing need to identify new effective therapeutic targets and improve immune therapies for these patients. In this regard, S-nitrosoglutathione reductase (GSNOR) is a denitrosylase enzyme that has been suggested to play a tumour suppressor role, although the mechanisms responsible are still largely unclear. Therefore, the main objective of this project was to understand the role of GSNOR in CRC tumorigenesis and its therapeutic implications. Firstly, we classified CRC tumours as GSNOR-high or low according to their GSNOR expression as assessed by immunohistochemistry (IHC). Accordingly, we found that GSNOR deficiency was associated with worse prognosis factors such as a larger tumour size at diagnosis, higher TNM stage, higher grade of tumour budding (TB), the CMS4 subtype, lower expression of the intestinal differentiation markers CDX2 and AE1/AE3 cytokeratin and a worse progression free survival (PFS) and overall survival (OS). We next investigated the differences in gene expression between CRC GSNOR-high and low tumours, uncovering significant alterations in metabolism and immune system pathways. Hence, GSNOR-deficient tumours were characterized by immune suppressive features and a dysregulation of their metabolism, favouring other metabolic pathways than OXPHOS.
2024-04-13 | GSE263844 | GEO
Project description:Targeting metabolism to improve immunotherapy in GSNOR-deficient colorectal cancer
| PRJEB74194 | ENA
Project description:Targeting metabolism to improve immunotherapy in GSNOR-deficient colorectal cancer
| PRJNA1099593 | ENA
Project description:The study was designed to explore the relationships between GSNOR/ADH5 expression and the tumor immune microenvironment
2023-03-17 | GSE227372 | GEO
Project description:AT-rich interactive domain-containing protein 1A (ARID1A), a core constituent of the switch/sucrose nonfermentable (SWI/SNF) complex, is mutated in approximately 10% of colorectal cancers. Whereas ARID1A deficiency corresponds to heightened immune activity in colorectal cancer, immune checkpoint inhibitors (ICI) have shown limited efficacy in these tumors. The discovery of targetable vulnerabilities associated with ARID1A deficiency in colorectal cancer could expand treatment options for patients. In this study, we demonstrated that arachidonic acid (AA) metabolism inhibitors synergize with ICIs in ARID1A-deficient colorectal cancer by enhancing the activity of CD8+ T cells and inhibiting vasculogenic mimicry. Epigenetic analysis using ATAC-seq and ChIP-qPCR revealed that the lack of ARID1A results in reduced levels of PTGS1 and PTGS2, the key enzymes that control the AA pathway. Low PTGS1 and PTGS2 expression generated a reliance on the remaining functionality of the AA pathway in ARID1A-deficient cells. The AA pathway inhibitor aspirin selectively inhibited the growth of ARID1A-deficient colorectal cancer, and aspirin sensitized tumors lacking ARID1A to immunotherapy. Together, these findings suggest that blocking AA metabolism can enhance immune responses against tumors by activating CD8+ T cells and inhibiting vasculogenic mimicry, which synergizes with ICIs to improve treatment of ARID1A-deficient colorectal cancer. Significance: The arachidonic acid pathway is a metabolic vulnerability in ARID1A-deficient colorectal cancer that can be targeted with aspirin to suppress tumor growth and enhance sensitivity to immunotherapy, providing a promising therapeutic strategy.
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Project description:Targeting METTL3 reprograms tumor microenvironment to improve cancer immunotherapy [RNA-seq]
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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.
2015-11-21 | E-GEOD-75233 | biostudies-arrayexpress
Project description:Currently, a marked number of clinical trials on cancer treatment have revealed the success of immunomodulatory therapies based on immune checkpoint inhibitors that activate tumor-specific T cells. However, the therapeutic efficacy of cancer immunotherapies is only restricted to a small fraction of patients. A deeper understanding of key mechanisms generating an immunosuppressive tumor microenvironment (TME) remains a major challenge for more effective antitumor immunity. There is a growing evidence that the TME supports inappropriate metabolic reprogramming that dampens T cell function, and therefore impacts the antitumor immune response and tumor progression. Notably, the immunosuppressive TME is characterized by a lack of crucial carbon sources critical for T cell function and increased inhibitory signals. Here, we summarize the basics of intrinsic and extrinsic metabolic remodeling and metabolic checkpoints underlying the competition between cancer and infiltrating immune cells for nutrients and metabolites. Intriguingly, the upregulation of tumor programmed death-L1 and cytotoxic T lymphocyte-associated antigen 4 alters the metabolic programme of T cells and drives their exhaustion. In this context, targeting both tumor and T cell metabolism can beneficially enhance or temper immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies.
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Project description:Homeostatic immunoregulatory mechanisms that prevent adverse effects of immune overaction can serve as barriers to successful anti-cancer immunity, representing attractive targets to improve cancer immunotherapy. Here, we demonstrated the role of the non-receptor tyrosine kinase Fes, abundantly expressed in immune cells, as an innate intracellular immune checkpoint. Host Fes-deficiency delayed tumor onset in a gene dose-dependent manner and improved tumor control, survival, doxorubicin efficacy, and anti-PD-1 therapy sensitization in murine triple-negative breast cancer and melanoma models. These effects were associated with a shift to an anti-tumorigenic immune microenvironment. Fes-deficient macrophages displayed increased Toll-like receptor signaling, proinflammatory cytokine production, antigen presentation to and activation of T cells, leading to increased cancer cell killing in vitro and tumor control in vivo. This study highlights Fes as an innate immune checkpoint with potential as a therapeutic target and a predictive biomarker to guide immune checkpoint inhibitor treatment.
2025-04-28 | GSE295079 | GEO
Project description:Fes-Deficient Macrophages Prime CD8+ T Cells to Stimulate Anti-tumor Immunity and Improve Immunotherapy Efficacy
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