瑞士洛桑大学 (UNIL) 和洛桑大学医院 (CHUV)George Coukos研究取得最新进展。他们发现髓样抗原呈递细胞壁龛维持抗肿瘤 T 细胞并通过 CD28 共刺激许可 PD-1 阻断。该项研究成果发表在2021年11月4日出版的《癌细胞》上。

在人类卵巢癌中，他们发现肿瘤特异性 CD8+ 肿瘤浸润淋巴细胞 (TIL)在肿瘤胰岛中积累，在那里它们与抗原结合并上调 PD-1，从而抑制它们的功能。然而，上皮内 PD-1+CD8+ TIL 可以是多功能的。 PD-1+ TIL 确实表现出持续的衰竭状态，CD28 共刺激水平不同，这是由上皮内肿瘤骨髓壁龛中的抗原呈递细胞 (APC) 提供的。

CD28 共刺激与耗竭 CD8+ TIL 的效应子适应性改善有关，并且是它们在 PD-1 阻断后激活所必需的，这也需要肿瘤髓系 APC。缺乏适当的 CD28 原位共刺激的耗竭TIL 无法对 PD-1 阻断产生反应，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。

据悉，TIL耗竭和对 PD-1 阻断反应的机制仍有部分未知。

附：英文原文

Title: Myeloid antigen-presenting cell niches sustain antitumor T cells and license PD-1 blockade via CD28 costimulation

Author: Jaikumar Duraiswamy, Riccardo Turrini, Aspram Minasyan, David Barras, Isaac Crespo, Alizée J. Grimm, Julia Casado, Raphael Genolet, Fabrizio Benedetti, Alexandre Wicky, Kalliopi Ioannidou, Wilson Castro, Christopher Neal, Amandine Moriot, Stéphanie Renaud-Tissot, Victor Anstett, Noémie Fahr, Janos L. Tanyi, Monika A. Eiva, Connor A. Jacobson, Kathleen T. Montone, Marie Christine Wulff Westergaard, Inge Marie Svane, Lana E. Kandalaft, Mauro Delorenzi, Peter K. Sorger, Anniina Frkkil, Olivier Michielin, Vincent Zoete, Santiago J. Carmona, Periklis G. Foukas, Daniel J. Powell, Sylvie Rusakiewicz, Marie-Agnès Doucey, Denarda Dangaj Laniti, George Coukos

Issue&Volume: 2021-11-04

Abstract: The mechanisms regulating exhaustion of tumor-infiltrating lymphocytes (TIL) and responsivenessto PD-1 blockade remain partly unknown. In human ovarian cancer, we show that tumor-specificCD8+ TIL accumulate in tumor islets, where they engage antigen and upregulate PD-1, whichrestrains 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 CD28costimulation, which is provided by antigen-presenting cells (APC) in intraepithelialtumor myeloid niches. CD28 costimulation is associated with improved effector fitnessof exhausted CD8+ TIL and is required for their activation upon PD-1 blockade, which also requirestumor 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-4blockade and tumor APC stimulation via CD40L.

DOI: 10.1016/j.ccell.2021.10.008

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00559-6