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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Koyama, S; Akbay, EA; Li, YY; Herter-Sprie, GS; Buczkowski, KA; Richards, WG; Gandhi, L; Redig, AJ; Rodig, SJ; Asahina, H; Jones, RE; Kulkarni, MM; Kuraguchi, M; Palakurthi, S; Fecci, PE; Johnson, BE; Janne, PA; Engelman, JA; Gangadharan, SP; Costa, DB; Freeman, GJ; Bueno, R; Hodi, FS; Dranoff, G; Wong, K-K; Hammerman, PS

Published Date

  • February 17, 2016

Published In

Volume / Issue

  • 7 /

Start / End Page

  • 10501 -

PubMed ID

  • 26883990

Pubmed Central ID

  • PMC4757784

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms10501


  • eng

Conference Location

  • England