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

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. PD-1 blockade can enhance antitumor responses in a subset of cases. Khleif and colleagues demonstrate that PD-1 blockade in the context of suboptimal T cell activation engenders a state of non-responsiveness but not when there is strong stimulation by vaccination.