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.

免疫检查点阻断为癌症治疗提供了范式转变，但这种方法的成功程度参差不齐；因此，迫切需要预测临床疗效的生物标志物。在这里，我们表明肿瘤微环境中 PD-1 ⁺ CD8 ⁺ T 细胞相对于 PD-1 ⁺调节性 T (T _reg ) 细胞的频率可以预测程序性细胞死亡蛋白 1 (PD-1) 的临床疗效) 阻断疗法，并且优于其他预测因子，包括 PD 配体 1 (PD-L1) 表达或肿瘤突变负荷。CD8 ⁺ T 细胞和 T _{reg 的}PD-1 表达细胞分别对效应子和免疫抑制功能产生负面影响。PD-1 阻断诱导功能失调的 PD-1 ⁺ CD8 ⁺ T 细胞的恢复和增强的 PD-1 ⁺ T _reg细胞介导的免疫抑制。通过 PD-1 阻断，效应 PD-1 ⁺ CD8 ⁺ T 细胞而不是 PD-1 ⁺ T _reg细胞的深刻再激活对于肿瘤消退是必要的。这些发现为 PD-1 阻断疗法提供了一个有希望的预测性生物标志物。