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Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation
Cancer Cell ( IF 48.8 ) Pub Date : 2021-11-04 , DOI: 10.1016/j.ccell.2021.10.008
Jaikumar Duraiswamy 1 , Riccardo Turrini 2 , Aspram Minasyan 2 , David Barras 3 , Isaac Crespo 2 , Alizée J Grimm 2 , Julia Casado 4 , Raphael Genolet 2 , Fabrizio Benedetti 2 , Alexandre Wicky 5 , Kalliopi Ioannidou 2 , Wilson Castro 2 , Christopher Neal 2 , Amandine Moriot 2 , Stéphanie Renaud-Tissot 6 , Victor Anstett 2 , Noémie Fahr 2 , Janos L Tanyi 1 , Monika A Eiva 7 , Connor A Jacobson 8 , Kathleen T Montone 9 , Marie Christine Wulff Westergaard 10 , Inge Marie Svane 10 , Lana E Kandalaft 6 , Mauro Delorenzi 11 , Peter K Sorger 8 , Anniina Färkkilä 12 , Olivier Michielin 5 , Vincent Zoete 2 , Santiago J Carmona 2 , Periklis G Foukas 13 , Daniel J Powell 7 , Sylvie Rusakiewicz 6 , Marie-Agnès Doucey 2 , Denarda Dangaj Laniti 2 , George Coukos 2
Affiliation  

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.



中文翻译:

骨髓抗原呈递细胞生态位维持抗肿瘤 T 细胞并通过 CD28 共刺激许可 PD-1 阻断

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。

更新日期:2021-12-13
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