Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Shohei Koyama, Esra A. Akbay, Yvonne Y. Li, Grit S. Herter-Sprie, Kevin A. Buczkowski, William G. Richards, Leena Gandhi, Amanda J. Redig, Scott J. Rodig, Hajime Asahina, Robert E. Jones, Meghana M. Kulkarni, Mari Kuraguchi, Sangeetha Palakurthi, Peter E. Fecci, Bruce E. Johnson, Pasi A. Janne, Jeffrey A. Engelman, Sidharta P. Gangadharan, Daniel B. Costa, Gordon J. Freeman, Raphael Bueno, F. Stephen Hodi, Glenn Dranoff (), Kwok-Kin Wong () and Peter S. Hammerman ()
Additional contact information
Shohei Koyama: Dana Farber Cancer Institute
Esra A. Akbay: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Yvonne Y. Li: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Grit S. Herter-Sprie: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Kevin A. Buczkowski: Dana Farber Cancer Institute
William G. Richards: Brigham and Women’s Hospital
Leena Gandhi: Dana Farber Cancer Institute
Amanda J. Redig: Dana Farber Cancer Institute
Scott J. Rodig: Brigham and Women’s Hospital
Hajime Asahina: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Robert E. Jones: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute
Meghana M. Kulkarni: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute
Mari Kuraguchi: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute
Sangeetha Palakurthi: Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute
Peter E. Fecci: Duke University Medical Center
Bruce E. Johnson: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Pasi A. Janne: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Jeffrey A. Engelman: Massachusetts General Hospital Cancer Center
Sidharta P. Gangadharan: Beth Israel Deaconess Medical Center
Daniel B. Costa: Beth Israel Deaconess Medical Center
Gordon J. Freeman: Dana Farber Cancer Institute
Raphael Bueno: Brigham and Women’s Hospital
F. Stephen Hodi: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Glenn Dranoff: Dana Farber Cancer Institute
Kwok-Kin Wong: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School
Peter S. Hammerman: Depatment of Medicine, Brigham and Women’s Hospital and Harvard Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-9

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10501

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