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.

中文翻译：

---

T细胞衰竭与免疫细胞溶解活性相关，以塑造发炎的肿瘤微环境。

缺乏对人类癌症中精疲力竭的T细胞的直接定量分析，其对基于检查点的治疗的预测价值仍然缺乏研究。为了精确免疫治疗的目的，我们试图系统地表征T细胞功能异常的癌症全景图和分子标志。在这里，我们通过分析原发性非小细胞肺癌（NSCLC）的PD-1高和PD-1阴性CD8 ⁺ T淋巴细胞之间的差异基因表达，定义了T细胞衰竭的转录特征，然后进行正相关测试与PDCD1在TCGA肺癌。耗尽CD8 ^+的78基因特征鉴定并验证了T细胞（GET），以反映跨越不同物种和疾病模型的机能失调的免疫状态。我们发现GET估计与30种实体瘤的肿瘤内免疫溶细胞活性（CYT）和T细胞炎症基因表达谱（GEP）显着相关。杂项肿瘤内在和外在特性，特别是白细胞比例，基因组异常，特定的突变特征和信号传导途径，与GET水平显着相关。此外，较高的GET表达预测了对免疫检查点抑制剂临床反应的可能性增加。这些发现凸显了全癌水平上T细胞衰竭与免疫细胞溶解活性之间的相互关系。导致的发炎的肿瘤微环境可能会进一步与其他分子和临床病理因素发生串扰，在免疫疗法生物标志物开发过程中应适当考虑。©2020英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版