Abstract 3488: MERTK inhibition regulates tumor-associated myeloid cell phenotypes and potentiates host-versus-lung cancer immunity

Abstract The TAM (TYRO3, AXL, MERTK) family receptor tyrosine kinases are important for clearing apoptotic cells and maintaining tissue homeostasis. They promote an immunosuppressive environment during cell clearance, which can be hijacked by tumor cells to promote immune evasion. This study aimed to determine how MERTK inhibition affects immune cells within the tumor microenvironment (TME) in lung cancer using a subcutaneous Kras-mutant murine lung cancer tumor model in wild-type (WT), Axl knock-out (KO), or Mertk KO mice. Tumor growth was inhibited in Mertk KO mice compared to WT mice, while Axl KO mice had no significant change in tumor growth. The anti-tumor effect observed in Mertk KO mice was lost in Mertk KO scid mice, which lack functional T and B cells, suggesting MERTK as an immunotherapeutic target in Kras-mutant lung cancer. MRX-2843 is a novel first-in-class MERTK-selective inhibitor that is currently being tested in phase 1/1b clinical trials. The murine cancer cell line used in this study did not express detectable MERTK and was unresponsive to MRX-2843 in vitro. However, in vivo treatment with MRX-2843 led to dose-dependent inhibition of tumor growth. Conditional knockout of Mertk in LysM expressing (i.e. myeloid) cells resulted in reduced tumor growth compared to tumors in WT mice. These data suggest that MERTK functions in myeloid cells to inhibit anti-tumor immunity, although contributions of homozygous LysM KO could not be eliminated in this study. Additionally, MERTK was only expressed in WT tumor myeloid cells ; myeloid cell MERTK was not detected in the TME in conditional Mertk KO mice. Furthermore, tumors from Mertk KO mice had evidence of increased antigen-presenting capacity with significantly increased numbers of tumor-associated macrophages expressing high levels of MHC-II and increased incidence of dendritic cells. Together these findings suggest that MERTK inhibits anti-tumor immunity by regulating myeloid cell functions and implicate MERTK as an immunotherapeutic target in Kras-mutant non-small cell lung cancer. Citation Format: Dan Yan, Xiaodong Wang, Stephen V. Frye, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham. MERTK inhibition regulates tumor-associated myeloid cell phenotypes and potentiates host-versus-lung cancer immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3488.