@article{30faed313b1d4ad98a567fc71cd87436,
title = "Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints",
abstract = "Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.",
author = "Shohei Koyama and Akbay, {Esra A.} and Li, {Yvonne Y.} and Herter-Sprie, {Grit S.} and Buczkowski, {Kevin A.} and Richards, {William G.} and Leena Gandhi and Redig, {Amanda J.} and Rodig, {Scott J.} and Hajime Asahina and Jones, {Robert E.} and Kulkarni, {Meghana M.} and Mari Kuraguchi and Sangeetha Palakurthi and Fecci, {Peter E.} and Johnson, {Bruce E.} and Janne, {Pasi A.} and Engelman, {Jeffrey A.} and Gangadharan, {Sidharta P.} and Costa, {Daniel B.} and Freeman, {Gordon J.} and Raphael Bueno and Hodi, {F. Stephen} and Glenn Dranoff and Wong, {Kwok Kin} and Hammerman, {Peter S.}",
note = "Funding Information: Competing financial interests: G.D. received sponsored research support from Funding Information: We thank Dana-Farber flow core facility (Suzan Lazo-Kallanian, John Daley, Kristen Cowens, Steven Paul) for help with flow cytometry anlaysis, Harvard Medical School Rodent Pathology Core for tissue processing and Brigham and Women{\textquoteright}s Pathology Core and Mei Zhang for help with tissue stainings, Xiaoen Wang for help with mouse MRI, and the Dana-Farber Center for Cancer Genome Discovery for RNA sequencing.P.S.H. is supported by a Clinical Investigator Award from the Damon Runyon Cancer Research Foundation, a Developmental Project Grant from NCI P50 CA090578 and the Starr Consortium for Cancer Research. K.-K.W. is supported by NIH/NCI P01 CA120964, 5R01CA163896-04, 1R01CA195740-01, 5R01CA140594-07, 5R01CA122794-10 and 5R01CA166480-04 grants and support from Gross-Loh Family Fund for Lung Cancer Research and Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute. S.K. is supported by Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award and The Kanae Foundation for the Promotion of Medical Science Fellowship Award. G.S.H.-S. is supported by the Deutsche Forschungsgemeinschaft (HE 6897/1-1) and the Claudia Adams Barr Program for Innovative Cancer Research. G.J.F. is supported by NIH R01AI08995. D.B.C. is supported by American Cancer Society grant RSG 11-186 and NCI grant CA090578. P.S.H., K.-K.W. J.A.E. and P.A.J. are supported by a Stand Up To Cancer—American Cancer Society Lung Cancer Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT17-15). Stand Up To Cancer is a programme of the Entertainment Industry Foundation.",
year = "2016",
month = feb,
day = "17",
doi = "10.1038/ncomms10501",
language = "English (US)",
volume = "7",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}