State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
Department of Thoracic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, PR China.
J Pathol. 2020 Jun;251(2):147-159. doi: 10.1002/path.5435. Epub 2020 May 19.
Direct quantification of exhausted T cells in human cancer is lacking, and its predictive value for checkpoint-based treatment remains poorly investigated. We sought to systematically characterize the pan-cancer landscape and molecular hallmarks of T-cell dysfunction for the purpose of precision immunotherapy. Here, we defined a transcriptional signature for T-cell exhaustion through analyzing differential gene expression between PD-1-high and PD-1-negative CD8 T lymphocytes from primary non-small cell lung cancer (NSCLC), followed by positive correlation tests with PDCD1 in TCGA lung carcinomas. A 78-gene signature for exhausted CD8 T cells (GET) was identified and validated to reflect dysfunctional immune state spanning different species and disease models. We discovered that GET estimation significantly correlated with intratumoral immune cytolytic activity (CYT) and T-cell-inflamed gene expression profile (GEP) across 30 solid tumor types. Miscellaneous tumor-intrinsic and -extrinsic properties, in particular leukocyte proportions, genomic abnormalities, specific mutational signatures, and signaling pathways, were notably associated with GET levels. Furthermore, higher GET expression predicted an increased likelihood of clinical response to immune checkpoint inhibitors. These findings highlight the interrelation between T-cell exhaustion and immune cytolytic activity at the pan-cancer scale. The resulting inflamed tumor microenvironment may further crosstalk with other molecular and clinicopathological factors, which should be properly considered during immunotherapy biomarker development. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
目前缺乏对人类癌症中耗竭 T 细胞的直接定量检测，其用于基于检查点的治疗的预测价值仍未得到充分研究。我们旨在通过系统地分析原发性非小细胞肺癌（NSCLC）中 PD-1 高表达和 PD-1 阴性 CD8 T 淋巴细胞之间的差异基因表达，来全面描述 T 细胞功能障碍的癌症全景和分子特征，以期实现精准免疫治疗。在此，我们通过分析原发性非小细胞肺癌（NSCLC）中 PD-1 高表达和 PD-1 阴性 CD8 T 淋巴细胞之间的差异基因表达，定义了一个 T 细胞耗竭的转录特征，随后通过与 TCGA 肺癌中的 PDCD1 进行正相关测试进行验证。确定并验证了一个 78 基因的耗竭 CD8 T 细胞（GET）特征基因集，以反映跨越不同物种和疾病模型的功能失调的免疫状态。我们发现，GET 估计值与 30 种实体瘤类型的肿瘤内免疫细胞毒性（CYT）和 T 细胞炎症基因表达谱（GEP）显著相关。各种肿瘤内在和外在特性，特别是白细胞比例、基因组异常、特定突变特征和信号通路，与 GET 水平显著相关。此外，GET 表达水平较高预示着对免疫检查点抑制剂治疗的临床反应的可能性增加。这些发现强调了在泛癌症范围内 T 细胞耗竭与免疫细胞毒性之间的相互关系。由此产生的炎症肿瘤微环境可能与其他分子和临床病理因素进一步相互作用，在免疫治疗生物标志物开发过程中应适当考虑这些因素。
