A single gene mutation predicts response to immune checkpoint blockade in ovarian clear cell carcinoma.

Abstract

There is a lack of genetic biomarkers for predicting response to immune checkpoint blockade (ICB) therapy in cancer. The recent discovery that loss-of-function mutations in the gene encoding the protein phosphatase 2A (PP2A) scaffold protein PPP2R1A confer sensitivity to immune checkpoint blockade in ovarian clear cell carcinoma, therefore represents a breakthrough. Mechanistically, mutations in the PPP2R1A gene induce a strong interferon gamma response in tumor cells, which enhances infiltration of activated CD8+ T cells into the tumor. The activity of these T cells is then fortified by ICB. Furthermore, preclinical studies have shown that PP2A inhibition leads to the generation of neoantigens by disrupting RNA splicing, and PP2A inhibition can remodel the immune microenvironment of tumors to enhance responses to ICB. The finding that loss-of-function PPP2R1A mutations predict benefit from immunotherapy also suggests that pharmacological inhibition of PP2A may act synergistically with ICB therapy.