A Novel Selective Axl/Mer/CSF1R Kinase Inhibitor as a Cancer Immunotherapeutic Agent Targeting Both Immune and Tumor Cells in the Tumor Microenvironment.

ABSTRACT: Although immune checkpoint blockade (ICB) represents a major breakthrough in cancer immunotherapy, only a limited number of patients with cancer benefit from ICB-based immunotherapy because most immune checkpoint inhibitors (ICIs) target only T cell activation. Therefore, targeting non-T cell components in the tumor microenvironment (TME) can help subvert resistance and increase the applications of ICB-based therapy. Axl and Mer are involved in the carcinogenesis of multiple types of cancer by modulating immune and biological behaviors within tumors. Colony stimulating factor 1 receptor (CSF1R) mediates tumorigenesis in the TME by enhancing tumor associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) infiltration, facilitating immune escape. Therefore, the simultaneous inhibition of Axl, Mer, and CSF1R kinases may improve therapeutic efficacy by targeting non-T cell components in the TME. Here, we present Q702, a selective, potent small molecule inhibitor targeting Axl, Mer, and CSF1R, for oral administration. Q702 induced antitumor activity in syngeneic tumor mouse models by: remodeling the TME toward immune stimulation; expanding M1 macrophage and CD8 T cell populations and decreasing M2 macrophage and MDSC populations in the TME; and increasing MHC class I and E-cadherin expression in tumor cells. Thus, Q702 may have great potential to broaden the coverage of populations benefiting from ICB-based immunotherapy.

SUBMITTER: Jeon Y 

PROVIDER: S-EPMC9563311 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature