T cell dysfunction is a hallmark of many cancers, but the basis for T cell dysfunction and the mechanisms by which antibody blockade of the inhibitory receptor PD-1 (anti-PD-1) reinvigorates T cells are not fully understood. Here we show that such therapy acts on a specific subpopulation of exhausted CD8⁺ tumor-infiltrating lymphocytes (TILs). Dysfunctional CD8⁺ TILs possess canonical epigenetic and transcriptional features of exhaustion that mirror those seen in chronic viral infection. Exhausted CD8⁺ TILs include a subpopulation of ‘progenitor exhausted’ cells that retain polyfunctionality, persist long term and differentiate into ‘terminally exhausted’ TILs. Consequently, progenitor exhausted CD8⁺ TILs are better able to control tumor growth than are terminally exhausted T cells. Progenitor exhausted TILs can respond to anti-PD-1 therapy, but terminally exhausted TILs cannot. Patients with melanoma who have a higher percentage of progenitor exhausted cells experience a longer duration of response to checkpoint-blockade therapy. Thus, approaches to expand the population of progenitor exhausted CD8⁺ T cells might be an important component of improving the response to checkpoint blockade.

T细胞功能障碍是许多癌症的标志，但是T细胞功能障碍的基础以及抑制受体PD-1（抗PD-1）的抗体重新激活T细胞的机制尚未完全清楚。在这里，我们表明，这种疗法作用于精疲力竭的CD8 ⁺肿瘤浸润淋巴细胞（TILs）的特定亚群。功能失调的CD8 ⁺ TIL具有典型的疲劳衰竭表观遗传和转录特征，与慢性病毒感染中的特征相似。精疲力竭的CD8 ⁺ TILs包括“祖细胞精疲力竭”的细胞亚群，这些细胞保留了多功能性，可以长期持续并分化为“终末精疲力竭”的TILs。结果，祖细胞耗尽了CD8 ⁺TIL比最终耗尽的T细胞更能控制肿瘤的生长。祖先精疲力竭的TIL可以对抗PD-1治疗产生反应，但终极精疲力竭的TIL则不能。黑色素瘤患者的祖细胞耗竭细胞百分比更高，对检查点封锁疗法的反应时间更长。因此，扩大祖细胞耗竭的CD8 ⁺ T细胞群体的方法可能是改善对检查站封锁反应的重要组成部分。