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Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor.
Nature Immunology ( IF 27.7 ) Pub Date : 2017-Dec-01 , DOI: 10.1038/ni.3868
Tomasz Maj , Wei Wang , Joel Crespo , Hongjuan Zhang , Weimin Wang , Shuang Wei , Lili Zhao , Linda Vatan , Irene Shao , Wojciech Szeliga , Costas Lyssiotis , J Rebecca Liu , Ilona Kryczek , Weiping Zou

Live regulatory T cells (Treg cells) suppress antitumor immunity, but how Treg cells behave in the metabolically abnormal tumor microenvironment remains unknown. Here we show that tumor Treg cells undergo apoptosis, and such apoptotic Treg cells abolish spontaneous and PD-L1-blockade-mediated antitumor T cell immunity. Biochemical and functional analyses show that adenosine, but not typical suppressive factors such as PD-L1, CTLA-4, TGF-β, IL-35, and IL-10, contributes to apoptotic Treg-cell-mediated immunosuppression. Mechanistically, apoptotic Treg cells release and convert a large amount of ATP to adenosine via CD39 and CD73, and mediate immunosuppression via the adenosine and A2A pathways. Apoptosis in Treg cells is attributed to their weak NRF2-associated antioxidant system and high vulnerability to free oxygen species in the tumor microenvironment. Thus, the data support a model wherein tumor Treg cells sustain and amplify their suppressor capacity through inadvertent death via oxidative stress. This work highlights the oxidative pathway as a metabolic checkpoint that controls Treg cell behavior and affects the efficacy of therapeutics targeting cancer checkpoints.

中文翻译:

氧化应激控制肿瘤中的调节性T细胞凋亡和抑制活性以及PD-L1阻滞性。

活的调节性T细胞(T reg细胞)抑制抗肿瘤免疫力,但是T reg细胞在新陈代谢异常的肿瘤微环境中的行为仍然未知。在这里,我们显示肿瘤T reg细胞经历凋亡,而这种凋亡性T reg细胞则消除了自发性和PD-L1阻断介导的抗肿瘤T细胞免疫力。生化和功能分析表明,腺苷而不是典型的抑制因子,例如PD-L1,CTLA-4,TGF-β,IL-35和IL-10,有助于凋亡的T reg细胞介导的免疫抑制。从机制上讲,凋亡的T reg细胞通过CD39和CD73释放并将大量ATP转化为腺苷,并通过腺苷和A介导免疫抑制2A途径。T reg细胞中的凋亡归因于其与NRF2相关的抗氧化剂系统薄弱以及对肿瘤微环境中游离氧物种的高度脆弱性。因此,数据支持了其中肿瘤T reg细胞通过氧化应激的无意死亡而维持并放大其抑制能力的模型。这项工作强调了氧化途径作为控制T reg细胞行为并影响靶向癌症检查点的疗法功效的代谢检查点。
更新日期:2017-11-10
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