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PLA2G2E is an inducer of IL-1B and CXCL2

ABSTRACT: The immunosuppressive tumor microenvironment (TME) limits the efficacy of antitumor immune responses. Myeloid cells within the TME are thought to be educated to establish this immunosuppressive milieu, although the underlying mechanisms remain incompletely understood. Here, we show that tumor cells reprogram myeloid cells to produce interleukin-1B (IL-1B) and CXC chemokine ligand 2 (CXCL2) through the phospholipase PLA2G2E. IL-1B and CXCL2 in turn fuel the immunosuppressive TME by recruiting myeloid-derived suppressor cells (MDSCs). Targeting PLA2G2E promotes tumor clearance in mice. Together, these findings identify PLA2G2E as a mediator of tumor cell-myeloid cell communication and define the major sources of IL-1B and CXCL2 in the TME, highlighting PLA2G2E as a potential therapeutic target in cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE348561 | GEO | 2026/10/02

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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PLA2G2E is an inducer of IL-1B and CXCL2

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