Open AccessPD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance
Author(s) -
Vivek Verma,
Rajeev Shrimali,
Shamim Ahmad,
Winjie Dai,
Hua Wang,
Sumin Lu,
Rahul Nandre,
Pankaj Gaur,
José Alejandro López,
Moshe Sade-Feldman,
Keren Yizhak,
Stacey L. Bjorgaard,
Keith T. Flaherty,
Jennifer A. Wargo,
Genevieve M. Boland,
Ryan J. Sullivan,
Gad Getz,
Scott A. Hammond,
Ming Tan,
Jingjing Qi,
Phillip Wong,
Taha Merghoub,
Jedd D. Wolchok,
Nir Hacohen,
John E. Janik,
Mikayel Mkrtichyan,
Seema Gupta,
Samir N. Khleif
Publication year - 2019
Publication title -
nature immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.074
H-Index - 388
eISSN - 1529-2916
pISSN - 1529-2908
DOI - 10.1038/s41590-019-0441-y
Subject(s) - priming (agriculture) , blockade , cd8 , cytotoxic t cell , immunology , t cell , antigen , pd l1 , cancer research , immune system , medicine , immunotherapy , biology , receptor , biochemistry , botany , germination , in vitro
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 + CD38 hi 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 + CD38 hi 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 + CD38 hi CD8 + cells that is reversed by optimal priming. PD-1 + CD38 hi 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.