AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1mutant NSCLC through expansion of TCF1+CD8 T cells

Mutations in STK11/LKB1in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1(L) mutation into murine lung adenocarcinomas driven by mutant Krasand Trp53loss (KP) resulted in an ICB refractory syngeneic KPLtumor. Mechanistically this occurred because KPLmutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPLtumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1mutant NSCLC.