Siska Peter J, Beckermann Kathryn E, Mason Frank M, Andrejeva Gabriela, Greenplate Allison R, Sendor Adam B, Chiang Yun-Chen J, Corona Armando L, Gemta Lelisa F, Vincent Benjamin G, Wang Richard C, Kim Bumki, Hong Jiyong, Chen Chiu-Lan, Bullock Timothy N, Irish Jonathan M, Rathmell W Kimryn, Rathmell Jeffrey C
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
JCI Insight. 2017 Jun 15;2(12). doi: 10.1172/jci.insight.93411.
Cancer cells can inhibit effector T cells (Teff) through both immunomodulatory receptors and the impact of cancer metabolism on the tumor microenvironment. Indeed, Teff require high rates of glucose metabolism, and consumption of essential nutrients or generation of waste products by tumor cells may impede essential T cell metabolic pathways. Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the tumor suppressor von Hippel-Lindau (VHL) and altered cancer cell metabolism. Here, we assessed how ccRCC influences the metabolism and activation of primary patient ccRCC tumor infiltrating lymphocytes (TIL). CD8 TIL were abundant in ccRCC, but they were phenotypically distinct and both functionally and metabolically impaired. ccRCC CD8 TIL were unable to efficiently uptake glucose or perform glycolysis and had small, fragmented mitochondria that were hyperpolarized and generated large amounts of ROS. Elevated ROS was associated with downregulated mitochondrial SOD2. CD8 T cells with hyperpolarized mitochondria were also visible in the blood of ccRCC patients. Importantly, provision of pyruvate to bypass glycolytic defects or scavengers to neutralize mitochondrial ROS could partially restore TIL activation. Thus, strategies to improve metabolic function of ccRCC CD8 TIL may promote the immune response to ccRCC.
癌细胞可通过免疫调节受体以及癌症代谢对肿瘤微环境的影响来抑制效应T细胞（Teff）。事实上，Teff需要高糖代谢率，而肿瘤细胞对必需营养物质的消耗或废物的产生可能会阻碍关键的T细胞代谢途径。透明细胞肾细胞癌（ccRCC）的特征是肿瘤抑制因子冯·希佩尔-林道（VHL）缺失以及癌细胞代谢改变。在此，我们评估了ccRCC如何影响原发性患者ccRCC肿瘤浸润淋巴细胞（TIL）的代谢和激活。CD8+ TIL在ccRCC中大量存在，但它们在表型上有所不同，并且在功能和代谢上均受损。ccRCC CD8+ TIL无法有效摄取葡萄糖或进行糖酵解，并且具有小的、碎片化的线粒体，这些线粒体超极化并产生大量活性氧（ROS）。ROS升高与线粒体超氧化物歧化酶2（SOD2）下调有关。线粒体超极化的CD8+ T细胞在ccRCC患者的血液中也可见。重要的是，提供丙酮酸以绕过糖酵解缺陷或使用清除剂来中和线粒体ROS可部分恢复TIL的激活。因此，改善ccRCC CD8+ TIL代谢功能的策略可能会促进对ccRCC的免疫反应。
