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PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance.

Verma, Vivek; Shrimali, Rajeev K; Ahmad, Shamim; Dai, Winjie; Wang, Hua; Lu, Sumin; Nandre, Rahul; Gaur, Pankaj; Lopez, Jose; Sade-Feldman, Moshe; Yizhak, Keren; Bjorgaard, Stacey L; Flaherty, Keith T; Wargo, Jennifer A; Boland, Genevieve M; Sullivan, Ryan J; Getz, Gad; Hammond, Scott A; Tan, Ming; Qi, Jingjing; Wong, Phillip; Merghoub, Taha; Wolchok, Jedd; Hacohen, Nir; Janik, John E; Mkrtichyan, Mikayel; Gupta, Seema; Khleif, Samir N.
Nat Immunol; 20(9): 1231-1243, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358999
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.
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