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. CostaGordon J. Freeman, Raphael Bueno, F. Stephen Hodi, Glenn Dranoff, Kwok Kin Wong, Peter S. Hammerman

Research output: Contribution to journalArticlepeer-review

1039 Scopus citations


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.

Original languageEnglish (US)
Article number10501
JournalNature communications
StatePublished - Feb 17 2016

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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