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

Cell Rep Med. 2022 Mar 15;3(3):100554. doi: 10.1016/j.xcrm.2022.100554.

Abstract

Mutations in STK11/LKB1 in 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 Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 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 KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 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 STK11/LKB1 mutant NSCLC.

Trial registration: ClinicalTrials.gov NCT03184571.

Keywords: Axl; NSCLC; STK11/LKB1 mutation; TCF1 CD8 T cells; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Animals
  • Axl Receptor Tyrosine Kinase
  • CD8-Positive T-Lymphocytes / metabolism
  • Carcinoma, Non-Small-Cell Lung* / drug therapy
  • Humans
  • Lung Neoplasms* / drug therapy
  • Mice
  • Programmed Cell Death 1 Receptor / genetics
  • Protein Serine-Threonine Kinases / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor Protein-Tyrosine Kinases / metabolism*

Substances

  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins
  • Receptor Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • AMP-Activated Protein Kinase Kinases
  • Axl Receptor Tyrosine Kinase

Associated data

  • ClinicalTrials.gov/NCT03184571