MERTK inhibition in the leukemia microenvironment promotes a therapeutic immune response to acute lymphoblastic leukemia

Abstract

Abstract T cell immunotherapy is effective in some, but not all cancers, and targeting the immunosuppressive, innate immune tumor microenvironment is one key to further advancement. During efferocytosis, activation of MERTK tyrosine kinase receptor in innate immune cells suppresses proinflammatory cytokines, stimulates immunosuppressive cytokines and upregulates co-inhibitory ligands. MERTK has also been validated as a therapeutic target in the tumor microenvironment in solid tumor models. To investigate immunoregulatory roles for MERTK in leukemia, we utilized pharmacologic and genetic inhibition of MERTK in a MERTK-negative syngeneic murine model of acute lymphoblastic leukemia (ALL). Treatment with MRX-2843, a potent, orally bioavailable, small molecule MERTK inhibitor, significantly reduced leukemic burden and prolonged median survival in wildtype mice (38 days post-treatment vs. 24 days in vehicle-treated mice, p>0.01). Similarly, overall survival was increased more than four-fold in Mertk−/− mice transplanted with leukemia (>80 days vs. 21 days in wild-type mice, p>0.0001), suggesting that the observed therapeutic activity is immune-mediated. Indeed, treatment with MRX-2843 abrogated expression of the immune co-inhibitory ligands PD-L1 and PD-L2 on CD11b+ monocytes/macrophages in the ALL microenvironment. Although T cells do not express MERTK, expression of the cognate PD-1 receptor was also reduced on CD8+ T cells and the frequency of FOXP3+CD4+ regulatory T cells was decreased in the leukemia microenvironment following MRX-2843 treatment. These data demonstrate several mechanisms by which MERTK can suppress anti-leukemia immunity and validate MERTK as a novel immunotherapeutic target in ALL.