PPP2R1A-mediated tumor-stromal adhesion as an unrecognized mechanism of immunosuppression

PPP2R1A, the predominant scaffolding subunit of the larger serine/threonine protein phosphatase 2A (PP2A), has been implicated in several solid tumors. Recently, somatic inactivating mutations in PPP2R1A have been shown to be associated with increased intratumoral inflammation and improved survival in patients undergoing dual immune checkpoint blockade for platinum-resistant ovarian clear-cell carcinoma. However, the structural and functional basis for this biological phenomenon has not yet been elucidated. We have previously reported PPP2R1A-mediated heterotypic-homodimeric protein-protein interactions between melanoma cells and lymphatic endothelial cells. Here, we demonstrate that PPP2R1A is also present on the surface of ovarian cancer cells. Moreover, we propose that the disruption of such tumor-lymphatic homodimeric interactions and thereby their interface may potentially be a causative factor for enhanced immune cell enrichment and inflammatory signaling within the tumor microenvironment, ultimately translating to improved survival with immune checkpoint inhibitors.