The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsiveness to PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specific CD8⁺ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, which restrains their functions. Intraepithelial PD-1⁺CD8⁺ TIL can be, however, polyfunctional. PD-1⁺ TIL indeed exhibit a continuum of exhaustion states, with variable levels of CD28 costimulation, which is provided by antigen-presenting cells (APC) in intraepithelial tumor myeloid niches. CD28 costimulation is associated with improved effector fitness of exhausted CD8⁺ TIL and is required for their activation upon PD-1 blockade, which also requires tumor myeloid APC. Exhausted TIL lacking proper CD28 costimulation in situ fail to respond to PD-1 blockade, and their response may be rescued by local CTLA-4 blockade and tumor APC stimulation via CD40L.

调节肿瘤浸润淋巴细胞 (TIL) 耗竭和对 PD-1 阻断反应的机制仍部分未知。在人类卵巢癌中，我们发现肿瘤特异性 CD8 ⁺ TIL 在肿瘤胰岛中积聚，在那里它们与抗原结合并上调 PD-1，从而抑制其功能。然而，上皮内 PD-1 ⁺ CD8 ^{+ TIL 可以是多功能的。}PD-1 ⁺ TIL 确实表现出连续的耗竭状态，具有不同水平的 CD28 共刺激，这是由上皮内肿瘤骨髓微环境中的抗原呈递细胞 (APC) 提供的。^{CD28 共刺激与耗尽的 CD8 +} TIL效应器适应性的改善有关，并且是 PD-1 阻断后激活它们所必需的，这也需要肿瘤骨髓 APC。缺乏适当的原位CD28 共刺激的耗尽 TIL无法对 PD-1 阻断做出反应，并且它们的反应可以通过局部 CTLA-4 阻断和通过 CD40L 的肿瘤 APC 刺激来挽救。