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

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

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Title: Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints
Author: Koyama, Shohei; Akbay, Esra A.; Li, Yvonne Y.; Herter-Sprie, Grit S.; Buczkowski, Kevin A.; Richards, William G.; Gandhi, Leena; Redig, Amanda J.; Rodig, Scott J.; Asahina, Hajime; Jones, Robert E.; Kulkarni, Meghana M.; Kuraguchi, Mari; Palakurthi, Sangeetha; Fecci, Peter E.; Johnson, Bruce E.; Janne, Pasi A.; Engelman, Jeffrey A.; Gangadharan, Sidharta P.; Costa, Daniel B.; Freeman, Gordon J.; Bueno, Raphael; Hodi, F. Stephen; Dranoff, Glenn; Wong, Kwok-Kin; Hammerman, Peter S.

Note: Order does not necessarily reflect citation order of authors.

Citation: Koyama, S., E. A. Akbay, Y. Y. Li, G. S. Herter-Sprie, K. A. Buczkowski, W. G. Richards, L. Gandhi, et al. 2016. “Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints.” Nature Communications 7 (1): 10501. doi:10.1038/ncomms10501. http://dx.doi.org/10.1038/ncomms10501.
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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.
Published Version: doi:10.1038/ncomms10501
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757784/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:26318574
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