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首页> 外文期刊>Nature >CD8~+ T cells regulate tumour ferroptosis during cancer immunotherapy
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CD8~+ T cells regulate tumour ferroptosis during cancer immunotherapy

机译：CD8〜+ T细胞在癌症免疫疗法期间调节肿瘤脱裂病变

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摘要

Cancer immunotherapy restores or enhances the effector function of CD8(+) T cells in the tumour microenvironment(1,2). CD8(+) T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways(3,4). Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide(5,6). Although it has been investigated in vitro(7,8), there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios(9,10). It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8(+) T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the antitumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFN gamma) released from CD8(+) T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system x(c)(-), impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system x(c)(- )was negatively associated, in cancer patients, with CD8(+) T cell signature, IFN gamma expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFN gamma and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.
机译：癌症免疫疗法恢复或增强肿瘤微环境中CD8（+）T细胞的效应功能（1,2）。 CD8（+）T细胞通过癌症免疫疗法透明肿瘤激活，主要通过穿孔蛋白 - 颗粒酶和Fas-Fas配体途径诱导细胞死亡（3,4）。脱裂病是一种细胞死亡的形式，其不同于凋亡和脂质过氧化物的铁依赖性积累的结果（5,6）。虽然它已经在体外进行了研究（7,8），但出现了出现的证据表明裂解病可能涉及各种病态场景（9,10）。目前尚不清楚脱毛裂菌是否参与T细胞免疫和癌症免疫疗法。在这里，我们表明，免疫疗法激活的CD8（+）T细胞增强了肿瘤细胞中的硬质抗性特异性脂质过氧化，并且增加的恶性凋亡有助于免疫疗法的抗肿瘤疗效。机械地，从CD8（+）T细胞中释放的干扰素γ（IFNγ）下调了SLC3A2和SLC7A11的表达，谷氨酸 - 胱氨酸抗原体系X（c）（ - ）的两个亚基，损害了肿瘤细胞的胱氨酸的摄取，因此，促进肿瘤细胞脂质过氧化和硬化。在小鼠模型中，通过囊肿（e）inase（e）inase（e）inase（含有胱氨酸和半胱氨酸的工程酶）结合检查点延迟协同增强的t细胞介导的抗肿瘤免疫并诱导肿瘤细胞中的恶性化酶。系统X（c）（ - ）的表达在癌症患者中，CD8（+）T细胞签名，IFNγ表达和患者结果产生了负相关。人类转录om在Nivolumab治疗前和期间的分析表明，临床益处与SLC3A2的表达和IFNγ和CD8增加相关。因此，T细胞促进的肿瘤脱裂化是一种抗肿瘤机制，并靶向该途径与检查点封闭的组合是潜在的治疗方法。

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  • 来源
    《Nature》 |2019年第7755期|270-274|共5页
  • 作者

    Wang Weimin; Green Michael; Choi Jae Eun; Gijon Miguel; Kennedy Paul D.; Johnson Jeffrey K.; Liao Peng; Lang Xueting; Kryczek Ilona; Sell Amanda; Xia Houjun; Zhou Jiajia; Li Gaopeng; Li Jing; Li Wei; Wei Shuang; Vatan Linda; Zhang Hongjuan; Szeliga Wojciech; Gu Wei; Liu Rebecca; Lawrence Theodore S.; Lamb Candice; Tanno Yuri; Cieslik Marcin; Stone Everett; Georgiou George; Chan Timothy A.; Chinnaiyan Arul; Zou Weiping;

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    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA|Univ Michigan Dept Radiat Oncol Sch Med Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA|Univ Michigan Sch Med Dept Pathol Ann Arbor MI 48109 USA|Univ Michigan Sch Med Michigan Ctr Translat Pathol Ann Arbor MI USA;

    Cayman Chem Co Ann Arbor MI USA;

    Cayman Chem Co Ann Arbor MI USA;

    Cayman Chem Co Ann Arbor MI USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA|Univ Michigan Dept Radiat Oncol Sch Med Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

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    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Univ Michigan Sch Med Dept Surg Ann Arbor MI 48109 USA|Univ Michigan Sch Med Rogel Canc Ctr Ctr Excellence Canc Immunol & Immunotherapy Ann Arbor MI 48109 USA;

    Columbia Univ Coll Phys & Surg Inst Canc Genet Dept Pathol & Cell Biol New York NY USA|Columbia Univ Coll Phys & Surg Herbert Irving Comprehens Canc Ctr New York NY USA;

    Univ Michigan Dept Obstet & Gynecol Sch Med Ann Arbor MI 48109 USA;

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