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

Huiyu Li, Zhida Liu, Longchao Liu, Hongyi Zhang, Chuanhui Han, Luc Girard, Hyunsil Park, Anli Zhang, Chunbo Dong, Jianfeng Ye, Austin Rayford, Michael Peyton, Xiaoguang Li, Kimberley Avila, Xuezhi Cao, Shuiqing Hu, Md Maksudul Alam, Esra A. Akbay, Luisa M. Solis, Carmen BehrensSharia Hernandez-Ruiz, Wei Lu, Ignacio Wistuba, John V. Heymach, Michael Chisamore, David Micklem, Hani Gabra, Gro Gausdal, James B. Lorens, Bo Li, Yang Xin Fu, John D. Minna, Rolf A. Brekken

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Article number100554
JournalCell Reports Medicine
Volume3
Issue number3
DOIs
StatePublished - Mar 15 2022

Keywords

  • Axl
  • immunotherapy
  • NSCLC
  • STK11/LKB1 mutation
  • TCF1 CD8 T cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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