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Tumor intrinsic METTL5 induces immune resistance in ovarian cancer by suppressing ferroptosis

ABSTRACT: Despite approval of immunotherapy for the treatment of ovarian cancer patients, the majority of patients fail to respond to immunotherapy or relapse following initial response. These failures may be attributed to immunosuppressive mechanisms co-opted by tumor cells. However, it is challenging to use conventional methods to systematically evaluate the potential of tumor intrinsic factors to act as immune regulators in patients with cancer. To identify immunosuppressive mechanisms in non-responders to cancer immunotherapy in ovarian cancer , we firstly performed an unbiased genome-wide CRISPR immune screens to explore tumor intrinsic factors which regulates ovarian cancer cell lines response to T cell mediated killing. Then we integrated the in vitro CRISPR screen results with multi-omics clinical data to generate a sub-library including top candidates for in vivo CRISPR screen to further evaluate the role of potential tumor intrinsic factors in regulating ovarian cancer cell response to immunotherapy with using the immune checkpoint blocker. Collectively, the data provide a rich resource of novel targets for rational immuno-oncology combinations.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE267542 | GEO | 2025/10/30

REPOSITORIES: GEO

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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.

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Tumor intrinsic METTL5 induces immune resistance in ovarian cancer by suppressing ferroptosis

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