AXL targeting restores PD-1 blockade sensitivity of <i>STK11/LKB1</i> mutant NSCLC through expansion of TCF1⁺ CD8 T cells.

Abstract

Mutations in <i>STK11/LKB1</i> in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a <i>Stk11/Lkb1</i> (<i>L</i>) mutation into murine lung adenocarcinomas driven by mutant <i>Kras</i> and <i>Trp53</i> loss (<i>KP</i>) resulted in an ICB refractory syngeneic <i>KPL</i> tumor. Mechanistically this occurred because <i>KPL</i> mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human <i>STK11/LKB1</i> mutant 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 <i>KPL</i> tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing <i>STK11/LKB1</i> mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified <i>STK11/LKB1</i> 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 <i>STK11/LKB1</i> mutant NSCLC.