@article{fd97084a20af443da51275a6f04ab2ef,
title = "AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells",
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.",
keywords = "Axl, immunotherapy, NSCLC, STK11/LKB1 mutation, TCF1 CD8 T cells",
author = "Huiyu Li and Zhida Liu and Longchao Liu and Hongyi Zhang and Chuanhui Han and Luc Girard and Hyunsil Park and Anli Zhang and Chunbo Dong and Jianfeng Ye and Austin Rayford and Michael Peyton and Xiaoguang Li and Kimberley Avila and Xuezhi Cao and Shuiqing Hu and Alam, {Md Maksudul} and Akbay, {Esra A.} and Solis, {Luisa M.} and Carmen Behrens and Sharia Hernandez-Ruiz and Wei Lu and Ignacio Wistuba and Heymach, {John V.} and Michael Chisamore and David Micklem and Hani Gabra and Gro Gausdal and Lorens, {James B.} and Bo Li and Fu, {Yang Xin} and Minna, {John D.} and Brekken, {Rolf A.}",
note = "Funding Information: This work was supported by a sponsored research agreement from BerGenBio ASA and NIH grants R01 CA243577 and U54 CA210181 (to R.A.B.); NIH SPORE P50 CA070907 , U54 CA224065 , and CPRIT RP160652 (to J.D.M.); RP150072 and RP180725 (to Y.-X.F.); NIH P30 CA142543 (to R.A.B., J.D.M., and Y.-X.F.), the Effie Marie Cain Foundation (to R.A.B.), and CPRIT training grant RP210041 (to H.L.). We would like to thank all the individuals who participated in this study. We also thank Zhaoning Wang, Amit Das, Kenneth Huffman, Huocong Huang, Jill Westcott, Long-Shan Li, and Jason Toombs for technical support, instruction, and advice. We thank the technical support of the following laboratory members of the Department of Translational Molecular Pathology Immunoprofiling Laboratory (TMP-IL) at MD Anderson Cancer Center: Mei Jiang, Khaja Khanand, and Jianling Zhou. We also thank the Animal Resources Center, Whole Brain Microscopy Facility, Flow Cytometry Facility, and Tissue Management ( P30 CA142543 ) cores at UT Southwestern for technical assistance and we acknowledge NIH P01 HD087150 for cord blood collection. Funding Information: This work was supported by a sponsored research agreement from BerGenBio ASA and NIH grants R01 CA243577 and U54 CA210181(to R.A.B.); NIH SPORE P50 CA070907, U54 CA224065, and CPRIT RP160652 (to J.D.M.); RP150072 and RP180725 (to Y.-X.F.); NIH P30 CA142543 (to R.A.B. J.D.M. and Y.-X.F.), the Effie Marie Cain Foundation (to R.A.B.), and CPRIT training grant RP210041(to H.L.). We would like to thank all the individuals who participated in this study. We also thank Zhaoning Wang, Amit Das, Kenneth Huffman, Huocong Huang, Jill Westcott, Long-Shan Li, and Jason Toombs for technical support, instruction, and advice. We thank the technical support of the following laboratory members of the Department of Translational Molecular Pathology Immunoprofiling Laboratory (TMP-IL) at MD Anderson Cancer Center: Mei Jiang, Khaja Khanand, and Jianling Zhou. We also thank the Animal Resources Center, Whole Brain Microscopy Facility, Flow Cytometry Facility, and Tissue Management (P30 CA142543) cores at UT Southwestern for technical assistance and we acknowledge NIH P01 HD087150 for cord blood collection. Conceptualization, H.L. Z.L. Y.-X.F. J.D.M. and R.A.B.; methodology, H.L. Z.L. H.Z. L.L. L.G. C.D. J.Y. X.L. and B.L.; investigation, H.L. Z.L. C.H. H.Z. L.L. L.G. H.P. A.Z. C.D. J.Y. A.R. D.G. M.P. X.L. K.A. X.C. L.S. C.B. S.H.-R. L.W. and D.M. writing, H.L. A.R. D.M. H.G. J.B.L. J.D.M. and R.A.B.; funding acquisition, Y.-X.F. J.D.M. and R.A.; resources, S.H. E.A.A. I.W. M.C. H.G. G.G. J.B.L. B.L. J.D.M. and J.V.H.; supervision, Y.-X.F. J.D.M. and R.A.B. This work was supported in part by a sponsored research agreement from BerGenBio ASA to R.A.B. A.R. D.M. H.G. and G.G. are current employees of BerGenBio ASA and J.B.L. is a former employee of BerGenBio ASA. M.C. is a current employee of Merck &Co. Inc. Kenilworth, NJ. J.D.M. receives licensing royalties from the NIH and UTSW for distribution of human tumor lines. H.L. Z.L. D.M. J.B.L. J.D.M. and R.A.B. are authors of a patent related to this study. The remaining authors have no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "15",
doi = "10.1016/j.xcrm.2022.100554",
language = "English (US)",
volume = "3",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "3",
}