MERTK inhibition selectively activates a DC - T-cell axis to provide anti-leukemia immunity

Abstract

TAM-family tyrosine kinases (TYRO3, AXL and MERTK) are potential cancer therapeutic targets. In previous studies MERTK inhibition in the immune microenvironment was therapeutically effective in a B-cell acute leukemia (B-ALL) model. Here, we probed anti-leukemia immune mechanisms and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Host Mertk knock-out or MERTK inhibitor MRX-2843 increased CD8α⁺ dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis. High MERTK or low DC gene expression were associated with poor prognosis in pediatric ALL patients, indicating the clinical relevance of these findings. MRX-2843 increased CD8⁺ T-cell numbers and prevented induction of exhaustion markers, implicating a DC - T-cell axis. Indeed, combined depletion of CD8α⁺ DCs and CD8⁺ T-cells was required to abrogate anti-leukemia immunity in Mertk^-/- mice. Tyro3^-/- mice were also protected against B-ALL, implicating TYRO3 as an immunotherapeutic target. In contrast to Mertk^-/- mice, Tyro3^-/- did not increase CD8α⁺ DCs with enhanced antigen-presentation capacity and therapeutic activity was less dependent on DCs, indicating a different immune mechanism. Axl^-/- did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.