美国马萨诸塞州总医院Thorsten R. Mempel课题组表明CXCR6 定位细胞毒性 T 细胞以接收肿瘤微环境中的关键存活信号。2021年8月2日国际知名学术期刊《细胞》发表了这一成果。
他们表明茎样细胞毒性 T 淋巴细胞 (CTL)向效应子样 CTL 的转化涉及主要的趋化重编程，包括趋化因子受体 CXCR6 的上调。这些受体将效应子样 CTL 定位在肿瘤基质的离散血管周围生态位中，该生态位被表达 CXCR6 配体 CXCL16 的 CCR7 + 树突细胞 (DC) 密集占据。CCR7 + DCs 也表达和反式呈递存活细胞因子白细胞介素 15 (IL-15)。CXCR6 表达和 IL-15 反式呈递对于肿瘤微环境中效应子样 CTL 的存活和局部扩张至关重要，以在进展为不可逆的功能障碍之前最大限度地发挥其抗肿瘤活性。这些观察结果揭示了一个细胞和分子检查点，它决定了抗肿瘤免疫反应的强度和结果。
据介绍，针对肿瘤的CTL反应由自我更新但也产生效应子样细胞的干细胞样记忆细胞维持。后者逐渐失去抗肿瘤活性并获得表观遗传固定的低功能状态，导致肿瘤耐受。
附：英文原文
Title: CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment
Author: Mauro Di Pilato, Raphael Kfuri-Rubens, Jasper N. Pruessmann, Aleksandra J. Ozga, Marius Messemaker, Bruno L. Cadilha, Ramya Sivakumar, Chiara Cianciaruso, Ross D. Warner, Francesco Marangoni, Esteban Carrizosa, Stefanie Lesch, James Billingsley, Daniel Perez-Ramos, Fidel Zavala, Esther Rheinbay, Andrew D. Luster, Michael Y. Gerner, Sebastian Kobold, Mikael J. Pittet, Thorsten R. Mempel
Issue&Volume: 2021-08-02
Abstract: Cytotoxic T lymphocyte (CTL) responses against tumors are maintained by stem-likememory cells that self-renew but also give rise to effector-like cells. The lattergradually lose their anti-tumor activity and acquire an epigenetically fixed, hypofunctionalstate, leading to tumor tolerance. Here, we show that the conversion of stem-likeinto effector-like CTLs involves a major chemotactic reprogramming that includes theupregulation of chemokine receptor CXCR6. This receptor positions effector-like CTLsin a discrete perivascular niche of the tumor stroma that is densely occupied by CCR7+ dendritic cells (DCs) expressing the CXCR6 ligand CXCL16. CCR7+ DCs also express and trans-present the survival cytokine interleukin-15 (IL-15). CXCR6 expression and IL-15trans-presentation are critical for the survival and local expansion of effector-like CTLsin the tumor microenvironment to maximize their anti-tumor activity before progressingto irreversible dysfunction. These observations reveal a cellular and molecular checkpointthat determines the magnitude and outcome of anti-tumor immune responses.
DOI: 10.1016/j.cell.2021.07.015
Source: https://www.cell.com/cell/fulltext/S0092-8674(21)00856-4