In a cohort of gastric and non-small cell lung cancer patients treated with anti-PD-1, responding patients had higher PD-1 expression on tumor-infiltrating CD8+ T cells and reduced PD-1 on effector Tregs. PD-1 expression on CD8+ T cells correlated with exposure to higher-affinity antigens. Anti-PD-1 mAb activated both PD-1+ Tregs and CD8+ T cells by restoring CD3/CD28 signaling and downstream ZAP70/AKT phosphorylation. The relative expression of PD-1 on CD8+ T cells and Tregs regulated proliferation in co-culture and tumor progression in vivo, and could predict anti-PD-1 patient responders better than prior biomarkers (AUC 0.933).
Contributed by Alex Najibi
ABSTRACT: Immune checkpoint blockade has provided a paradigm shift in cancer therapy, but the success of this approach is very variable; therefore, biomarkers predictive of clinical efficacy are urgently required. Here, we show that the frequency of PD-1(+)CD8(+) T cells relative to that of PD-1(+) regulatory T (T(reg)) cells in the tumor microenvironment can predict the clinical efficacy of programmed cell death protein 1 (PD-1) blockade therapies and is superior to other predictors, including PD ligand 1 (PD-L1) expression or tumor mutational burden. PD-1 expression by CD8(+) T cells and T(reg) cells negatively impacts effector and immunosuppressive functions, respectively. PD-1 blockade induces both recovery of dysfunctional PD-1(+)CD8(+) T cells and enhanced PD-1(+) T(reg) cell-mediated immunosuppression. A profound reactivation of effector PD-1(+)CD8(+) T cells rather than PD-1(+) T(reg) cells by PD-1 blockade is necessary for tumor regression. These findings provide a promising predictive biomarker for PD-1 blockade therapies.