Thoracic Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Rev Clin Oncol. 2022 Dec;19(12):775-790. doi: 10.1038/s41571-022-00689-z. Epub 2022 Oct 10.
Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.
免疫疗法在癌症治疗方面取得了显著的临床进展。T 细胞是当前癌症免疫疗法（包括免疫检查点抑制剂和过继细胞疗法）疗效的关键。然而，癌症与 T 细胞耗竭有关，T 细胞耗竭是一种低功能状态，其特征是 T 细胞效应功能和自我更新能力逐渐丧失。在肿瘤微环境中“不耗竭”T 细胞通常被认为是免疫检查点抑制剂的一种关键作用机制，而 T 细胞耗竭被认为是细胞免疫疗法的一种耐药途径。几项精心设计的研究为控制 T 细胞耗竭的转录和表观遗传程序提供了重要的见解。在这篇综述中，我们强调了与 T 细胞耗竭的免疫生物学相关的最新发现，这些发现提供了比低功能状态完全不可取更为细致的观点。我们回顾了证据表明，T 细胞耗竭可能既是肿瘤控制不良的反映，也是其原因。此外，我们假设，在慢性抗原刺激的某些情况下，中断耗竭程序可能会损害 T 细胞的持久性。因此，优先考虑干预措施来减轻 T 细胞耗竭的发展，包括正交细胞减少疗法和新型细胞工程策略，最终可能会带来更好的临床结果，并在癌症免疫治疗方面取得最大进展。
