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

被引:53
|
作者
Li, Huiyu [1 ,2 ]
Liu, Zhida [3 ,16 ]
Liu, Longchao [3 ]
Zhang, Hongyi [4 ]
Han, Chuanhui [3 ]
Girard, Luc [1 ,13 ]
Park, Hyunsil [1 ]
Zhang, Anli [3 ]
Dong, Chunbo [3 ]
Ye, Jianfeng [4 ]
Rayford, Austin [5 ,11 ]
Peyton, Michael [1 ]
Li, Xiaoguang [3 ]
Avila, Kimberley [1 ]
Cao, Xuezhi [3 ]
Hu, Shuiqing [7 ]
Alam, Md Maksudul [3 ]
Akbay, Esra A. [3 ]
Solis, Luisa M. [8 ]
Behrens, Carmen [9 ]
Hernandez-Ruiz, Sharia [8 ]
Lu, Wei [8 ]
Wistuba, Ignacio [8 ]
Heymach, John, V [9 ]
Chisamore, Michael [10 ]
Micklem, David [5 ]
Gabra, Hani [5 ]
Gausdal, Gro [5 ]
Lorens, James B. [11 ]
Li, Bo [4 ,12 ]
Fu, Yang-Xin [3 ,12 ]
Minna, John D. [1 ,2 ,13 ,14 ,15 ]
Brekken, Rolf A. [1 ,2 ,6 ,13 ,14 ]
机构
[1] UT Southwestern Med Ctr, Hamon Ctr Therapeut Oncol Res, 6000 Harry Hines Blvd, Dallas, TX 75390 USA
[2] UT Southwestern Med Ctr, Canc Biol Grad Program, Dallas, TX 75390 USA
[3] UT Southwestern Med Ctr, Dept Pathol, 6000 Harry Hines Blvd, Dallas, TX 75390 USA
[4] UT Southwestern Med Ctr, Lyda Hill Dept Bioinformat, Dallas, TX 75390 USA
[5] BerGenBio ASA, Bergen, Norway
[6] UT Southwestern Med Ctr, Dept Surg, Dallas, TX 75390 USA
[7] UT Southwestern Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA
[8] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX 77030 USA
[9] Univ Texas MD Anderson Canc Ctr, Thorac Head & Neck Med Oncol, Houston, TX 77030 USA
[10] Merck & Co Inc, Kenilworth, NJ 07033 USA
[11] Univ Bergen, Ctr Canc Biomarkers, Norwegian Ctr Excellence, Dept Biomed, Bergen, Norway
[12] UT Southwestern Med Ctr, Dept Immunol, Dallas, TX 75390 USA
[13] UT Southwestern Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA
[14] UT Southwestern Med Ctr, Harold C Simmons Comprehens Canc Ctr, Dallas, TX 75390 USA
[15] UT Southwestern Med Ctr, Dept Internal Med, Dallas, TX 75390 USA
[16] Shanxi Acad Adv Res & Innovat, Taiyuan 030032, Peoples R China
关键词
DENDRITIC CELLS; I INTERFERON; IMMUNE-RESPONSE; INNATE; KINASE; INHIBITION; RECEPTORS; LKB1;
D O I
10.1016/j.xcrm.2022.100554
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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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收藏
页数:21
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