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

• Published in: Cell reports. Medicine Vol. 3; no. 3; p. 100554
• Main Authors: Li, Huiyu, Liu, Zhida, Liu, Longchao, Zhang, Hongyi, Han, Chuanhui, Girard, Luc, Park, Hyunsil, Zhang, Anli, Dong, Chunbo, Ye, Jianfeng, Rayford, Austin, Peyton, Michael, Li, Xiaoguang, Avila, Kimberley, Cao, Xuezhi, Hu, Shuiqing, Alam, Md Maksudul, Akbay, Esra A., Solis, Luisa M., Behrens, Carmen, Hernandez-Ruiz, Sharia, Lu, Wei, Wistuba, Ignacio, Heymach, John V., Chisamore, Michael, Micklem, David, Gabra, Hani, Gausdal, Gro, Lorens, James B., Li, Bo, Fu, Yang-Xin, Minna, John D., Brekken, Rolf A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-03-2022; Elsevier
• Subjects: AMP-Activated Protein Kinase Kinases; Animals; Axl; Axl Receptor Tyrosine Kinase; Carcinoma, Non-Small-Cell Lung - drug therapy; CD8-Positive T-Lymphocytes - metabolism; Humans; immunotherapy; Lung Neoplasms - drug therapy; Mice; NSCLC; Programmed Cell Death 1 Receptor - genetics; Protein Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins - metabolism; Receptor Protein-Tyrosine Kinases - metabolism; STK11/LKB1 mutation; TCF1 CD8 T cells; TCF1 CD8 T cells; STK11/LKB1 mutation; Axl; NSCLC; immunotherapy
• ISSN: 2666-3791; 2666-3791
• DOI: 10.1016/j.xcrm.2022.100554

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.
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•Lack of TCF1+ CD8 T cells underlies poor response of STK11 mutant NSCSLC to anti-PD-1•Axl inhibition induces type I interferon and expansion of TCF1+ CD8 T cells•Axl inhibition sensitizes STK11/LKB1 mutant NSCLC to anti-PD-1 therapy•Preliminary clinical data supports inhibition of Axl and PD-1 in STK11 mutant NSCLC
Li et al. provide mechanistic insight into why lung cancers with a common mutation (LKB1/STK11) are largely insensitive to immune therapy. The authors also demonstrate that inhibition of AXL activity in dendritic cells can restore sensitivity to immune therapy in LKB1/STK11 mutant lung cancer.