PPP2R1A mutations portend improved survival after cancer immunotherapy

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.