Ovarian Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, University of Lausanne (UNIL) and Lausanne University Hospital (CHUV), 1011 Lausanne, Switzerland.
Cancer Cell. 2021 Dec 13;39(12):1623-1642.e20. doi: 10.1016/j.ccell.2021.10.008. Epub 2021 Nov 4.
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-1CD8 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，我们表明肿瘤特异性 CD8 TIL 聚集在肿瘤胰岛中，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-1CD8 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，这由上皮内肿瘤髓样龛中的抗原呈递细胞 (APC) 提供。CD28 共刺激与耗竭的 CD8 TIL 的效应器适应性提高相关，并且是其在 PD-1 阻断时激活所必需的，这也需要肿瘤髓样 APC。在原位缺乏适当 CD28 共刺激的耗竭 TIL 无法对 PD-1 阻断产生反应，并且它们的反应可以通过局部 CTLA-4 阻断和通过 CD40L 刺激肿瘤 APC 来挽救。
