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PPP2R1A mutations portend improved survival after cancer immunotherapy

ABSTRACT: Immune checkpoint blockade (ICB) therapy is effective against many cancers, though resistance remains a major issue and novel strategies are needed to improve clinical outcomes. We studied ICB response in a cohort of patients with ovarian clear cell carcinoma (OCCC), a cancer type that poses significant clinical challenges and lacks effective therapies. Here we observed significantly prolonged overall and progression-free survival in patients with tumors harboring PPP2R1A inactivating mutations (PPP2R1Amut). Importantly, findings were validated in additional ICB-treated patient cohorts across multiple cancer types. Translational analyses from tumor biopsies demonstrated enhanced interferon-gamma signaling, and presence of tertiary lymphoid structures at baseline, as well as enhanced immune infiltration and expansion of CD45RO+ CD8+ T cells in the tumor neighborhood upon ICB treatment, in PPP2R1Amut tumors. Parallel pre-clinical investigations showed that targeting PPP2R1A (via pharmacologic inhibition or knockdown) in in vitro and in vivo models was associated with improved survival in the setting of treatment with several forms of immunotherapy, including chimeric antigen receptor-T cell therapy and ICB. Results from these studies suggest that therapeutic targeting of PPP2R1A may represent an effective strategy to improve patient outcomes following ICB or other forms of immunotherapy, though additional mechanistic and therapeutic insights are needed.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276284 | GEO | 2025/05/01

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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PPP2R1A mutations portend improved survival after cancer immunotherapy

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