TMIC-65. PP2A/STRN4 NEGATIVELY REGULATES STING-TYPE I IFN SIGNALING IN GLIOMA ASSOCIATED MACROPHAGES THROUGH YAP/TAZ

Abstract Glioma associated Macrophages/microglia (GAMs) are the predominant immune cells in the tumor microenvironment and drive immunosuppression. Strategies depleting GAMs have not demonstrated efficacy in clinical trials for GBM. It is critical to identify the underlying mechanisms how GAMs mediate immunosuppression. STING agonist, which activates the Type I IFN signaling in myeloid cells, is a promising strategy but also have shown limited efficacy in clinical trials. Here, we report that protein phosphatase 2A (PP2A), with its specific B regulatory subunit Striatin 4 (STRN4), negatively regulated STING-Type I IFN in GAMs. Mice with macrophage PP2A deficiency exhibited improved glioma survival with radiation, which is known to activate STING. The glioma microenvironment showed decreased immunosuppressive and increased IFN-activated macrophages and CD8+ T cells. Mechanistically, we demonstrated that Hippo kinase MST1/2 was required for STING activation in macrophages. STING agonists induced dissociation of PP2A from MST1/2 in normal macrophages, but not in glioma conditioned macrophages. Furthermore, our data showed that STRN4 mediated PP2A binding to and dephosphorylation of Hippo kinase MST1/2, resulting in stabilization of YAP/TAZ to antagonize STING activation. We are also the first to demonstrate that in human GBM patients, YAP/TAZ signature was highly expressed in GAMs but not in non tumor macrophages. We also demonstrated that PP2A/STRN4 deficiency in macrophages reduced YAP/TAZ expression and sensitized glioma -conditioned macrophages to STING stimulation. In summary, we demonstrated that PP2A/STRN4- YAP/TAZ has, in our opinion, been an unappreciated mechanism that mediates immunosuppression in glioma-associated macrophages, and targeting the PP2A/STRN4-YAP/TAZ axis can sensitize glioma to immunotherapy.