PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance Journal Article


Authors: Verma, V.; Shrimali, R. K.; Ahmad, S.; Dai, W.; Wang, H.; Lu, S.; Nandre, R.; Gaur, P.; Lopez, J.; Sade-Feldman, M.; Yizhak, K.; Bjorgaard, S. L.; Flaherty, K. T.; Wargo, J. A.; Boland, G. M.; Sullivan, R. J.; Getz, G.; Hammond, S. A.; Tan, M.; Qi, J.; Wong, P.; Merghoub, T.; Wolchok, J.; Hacohen, N.; Janik, J. E.; Mkrtichyan, M.; Gupta, S.; Khleif, S. N.
Article Title: PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1(+)CD38(hi) cells and anti-PD-1 resistance
Abstract: Understanding resistance to antibody to programmed cell death protein 1 (PD-1; anti-PD-1) is crucial for the development of reversal strategies. In anti-PD-1-resistant models, simultaneous anti-PD-1 and vaccine therapy reversed resistance, while PD-1 blockade before antigen priming abolished therapeutic outcomes. This was due to induction of dysfunctional PD-1+CD38hi CD8+ cells by PD-1 blockade in suboptimally primed CD8 cell conditions induced by tumors. This results in erroneous T cell receptor signaling and unresponsiveness to antigenic restimulation. On the other hand, PD-1 blockade of optimally primed CD8 cells prevented the induction of dysfunctional CD8 cells, reversing resistance. Depleting PD-1+CD38hi CD8+ cells enhanced therapeutic outcomes. Furthermore, non-responding patients showed more PD-1+CD38+CD8+ cells in tumor and blood than responders. In conclusion, the status of CD8+ T cell priming is a major contributor to anti-PD-1 therapeutic resistance. PD-1 blockade in unprimed or suboptimally primed CD8 cells induces resistance through the induction of PD-1+CD38hi CD8+ cells that is reversed by optimal priming. PD-1+CD38hi CD8+ cells serve as a predictive and therapeutic biomarker for anti-PD-1 treatment. Sequencing of anti-PD-1 and vaccine is crucial for successful therapy. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
Journal Title: Nature Immunology
Volume: 20
Issue: 9
ISSN: 1529-2908
Publisher: Nature Publishing Group  
Date Published: 2019-09-01
Start Page: 1231
End Page: 1243
Language: English
DOI: 10.1038/s41590-019-0441-y
PUBMED: 31358999
PROVIDER: scopus
PMCID: PMC7472661
DOI/URL:
Notes: Correction issued, see DOI: 10.1038/s41590-019-0519-6 -- Source: Scopus
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  1. Jedd D Wolchok
    815 Wolchok
  2. Taha Merghoub
    293 Merghoub
  3. Phillip Wong
    56 Wong
  4. Jingjing Qi
    6 Qi