PDF(Pubmed)
Abstract：
Use of chimeric antigen receptor (CAR) T cells to treat B cell lymphoma and leukemia has been remarkably successful. Unfortunately, the therapeutic efficacy of CAR T cells against solid tumors is very limited, with immunosuppression by the pro-oxidative tumor microenvironment (TME) a major contributing factor. High levels of reactive oxygen species are well-tolerated by tumor cells due to their elevated expression of antioxidant proteins; however, this is not the case for T cells, which consequently become hypo-responsive. The aim of this study was to improve CAR T cell efficacy in solid tumors by empowering the antioxidant capacity of CAR T cells against the pro-oxidative TME. To this end, HER2-specific human CAR T cells stably expressing two antioxidant systems: thioredoxin-1 (TRX1), and glutaredoxin-1 (GRX1) were generated and characterized. Thereafter, antitumor functions of CAR T cells were evaluated under control or pro-oxidative conditions. To provide insights into the role of antioxidant systems, gene expression profiles as well as global protein oxidation were analyzed. Our results highlight that TRX1 is pivotal for T cell redox homeostasis. TRX1 expression allows CAR T cells to retain their cytolytic immune synapse formation, cytokine release, proliferation, and tumor cell-killing properties under pro-oxidative conditions. Evaluation of differentially expressed genes and the first comprehensive redoxosome analysis of T cells by mass spectrometry further clarified the underlying mechanisms. Taken together, enhancement of the key antioxidant TRX1 in human T cells opens possibilities to increase the efficacy of CAR T cell treatment against solid tumors.
摘要：
使用嵌合抗原受体(CAR)T细胞治疗B细胞淋巴瘤和白血病已经非常成功。不幸的是,CART细胞对实体瘤的治疗效果非常有限，与促氧化肿瘤微环境（TME）的免疫抑制有关。由于抗氧化蛋白的表达升高，高水平的活性氧可被肿瘤细胞耐受；然而，T细胞的情况并非如此,因此变得反应迟钝。这项研究的目的是通过增强CART细胞对抗促氧化TME的抗氧化能力来提高实体肿瘤中的CART细胞功效。为此,HER2特异性人CART细胞稳定表达两个抗氧化系统：硫氧还蛋白-1（TRX1），生成并表征了谷氧还蛋白-1（GRX1）。此后,在对照或促氧化条件下评估CART细胞的抗肿瘤功能.提供对抗氧化剂系统的作用的见解，基因表达谱以及整体蛋白质氧化进行了分析。我们的结果强调TRX1对于T细胞氧化还原稳态至关重要。TRX1表达允许CART细胞保留其细胞溶解免疫突触形成，细胞因子释放，扩散,和促氧化条件下的肿瘤细胞杀伤特性。对差异表达基因的评估和通过质谱对T细胞的首次全面的redoxosome分析进一步阐明了潜在的机制。一起来看,增强人类T细胞中的关键抗氧化剂TRX1打开了增加CART细胞治疗对抗实体瘤的功效的可能性。
