CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation.
Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation.
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调节TIL（肿瘤浸润淋巴细胞）耗竭及对PD-1阻断反应性的机制仍部分未知。在人类卵巢癌中，我们显示肿瘤特异性CD8+ TIL积聚在肿瘤岛内，在那里它们接触抗原并上调PD-1，从而限制其功能。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，其CD28共刺激水平可变，CD28共刺激由上皮内肿瘤髓系微环境中的抗原呈递细胞（APC）提供。CD28共刺激与耗竭CD8+ TIL效应适应性的改善相关，并且是其在PD-1阻断后活化所必需的，后者也需要肿瘤髓系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，其反应可能通过局部CTLA-4阻断和经CD40L刺激肿瘤APC而得以挽救。
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.
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