AXL targeting restores PD-1 blockade sensitivity of mutant NSCLC through expansion of TCF1 CD8 T cells.

Mutations in in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a () mutation into murine lung adenocarcinomas driven by mutant and loss () resulted in an ICB refractory syngeneic tumor. Mechanistically this occurred because mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1PD-1CD8 T cells, restoring therapeutic response to PD-1 ICB in tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in mutant NSCLC.