Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
Cell Mol Immunol. 2021 Feb;18(2):385-397. doi: 10.1038/s41423-020-0427-6. Epub 2020 Apr 24.
Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8 T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8 T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8 T cells (CD8 TILs) obtained from non-small-cell lung cancer patients. Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8 TILs. Furthermore, we found that human CD28CD8 but not CD28CD8 TILs responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 costimulation in human CD8 TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8 TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28PD-1CD8 TILs exhibited characteristics of terminally exhausted CD8 T cells with low TCF1 expression. Notably, CD28PD-1CD8 TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced the proliferation of CD28PD-1CD8 TILs as well as CD28PD-1CD8 TILs. Taken together, these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8 TILs with a TCF1 signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.
阻断程序性死亡受体-1（PD-1）可使衰竭的 CD8 T 细胞重新激活，从而导致癌症患者肿瘤消退。最近，在小鼠模型中，PD-1 阻断后衰竭的 CD8 T 细胞的重新激活被证明是依赖于 CD28 的。在此，我们使用从非小细胞肺癌患者中获得的肿瘤浸润性 CD8 T 细胞（CD8 TIL），研究了 CD28 在抗 PD-1 抗体诱导的人 T 细胞再激活中的作用。单细胞分析显示了小鼠和人 CD8 TIL 之间 CD28 的明显表达模式。此外，我们发现，人 CD28CD8 但不是 CD28CD8 TIL 对 PD-1 阻断有反应，而不管 B7/CD28 阻断如何，这表明人 CD8 TIL 中的 CD28 共刺激对于 PD-1 阻断诱导的再激活是可有可无的，并且 CD28 表达的丧失可作为抗 PD-1 抗体无反应性 CD8 TIL 的标志物。从转录和表型上看，PD-1 阻断无反应性的人 CD28PD-1CD8 TIL 表现出具有低 TCF1 表达的终末衰竭 CD8 T 细胞的特征。值得注意的是，CD28PD-1CD8 TIL 保留了对 IL-15 作出反应的机制，而 IL-15 处理增强了 CD28PD-1CD8 TIL 和 CD28PD-1CD8 TIL 的增殖。总之，这些结果表明，CD28 表达的丧失是具有 TCF1 特征的 PD-1 阻断无反应性人 CD8 TIL 的标志物，并为联合使用 IL-15 和抗 PD-1 抗体提供了机制上的见解。
