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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中调节肿瘤的肥大

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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：癌症免疫疗法可恢复或增强肿瘤微环境中CD8（+）T细胞的效应子功能（1,2）。癌症免疫疗法激活的CD8（+）T细胞主要通过穿孔素颗粒酶和Fas-Fas配体途径诱导细胞死亡来清除肿瘤（3,4）。 Ferroptosis是细胞死亡的一种形式，它不同于凋亡，是铁依赖的脂质过氧化物的积累造成的（5,6）。尽管已经在体外进行了研究（7,8），但有新的证据表明，肥大症可能与多种病理情况有关（9,10）。目前尚不清楚T细胞免疫和癌症免疫疗法是否涉及肥大症以及如何发病。在这里，我们显示免疫疗法激活的CD8（+）T细胞增强了肿瘤细胞中特定于肥大症的脂质过氧化作用，而肥大症的增加有助于免疫疗法的抗肿瘤功效。从机制上讲，从CD8（+）T细胞释放的干扰素γ（IFNγ）下调SLC3A2和SLC7A11（谷氨酸-胱氨酸逆转运蛋白系统x（c）（-）的两个亚基）的表达，从而损害肿瘤细胞对胱氨酸的吸收，结果，促进了肿瘤细胞脂质过氧化和肥大症。在小鼠模型中，胱抑素酶（一种能降解胱氨酸和半胱氨酸的工程酶）与检查点封锁相结合，可消除胱氨酸或半胱氨酸，从而协同增强T细胞介导的抗肿瘤免疫力，并在肿瘤细胞中诱导肥大症。在癌症患者中，系统x（c）（-）的表达与CD8（+）T细胞标志，IFNγ表达和患者预后呈负相关。在nivolumab治疗之前和期间进行的人类转录组分析表明，临床益处与SLC3A2的表达减少以及IFNγ和CD8的增加有关。因此，T细胞促进的肿瘤肥大症是一种抗肿瘤机制，与该检查点结合使用靶向该途径是一种潜在的治疗方法。

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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;

  • 作者单位

    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;

    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;

    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;

    Univ Michigan, Dept Radiat Oncol, Sch Med, Ann Arbor, MI 48109 USA;

    Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA|Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA;

    Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA|Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA;

    Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA|Univ Michigan, Sch Med, Dept Computat Med & Bioinformat, Ann Arbor, MI USA;

    Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA|Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA;

    Univ Texas Austin, Dept Chem Engn, Austin, TX 78712 USA|Univ Texas Austin, Dept Mol Biosci, Austin, TX 78712 USA;

    Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, Immunogen & Precis Oncol Platform, 1275 York Ave, New York, NY 10021 USA;

    Univ Michigan, Sch Med, Dept Pathol, Ann Arbor, MI 48109 USA|Univ Michigan, Sch Med, Michigan Ctr Translat Pathol, Ann Arbor, MI USA|Univ Michigan, Sch Med, Howard Hughes Med Inst, 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 Pathol, Ann Arbor, MI 48109 USA|Univ Michigan, Sch Med, Grad Program Immunol, Ann Arbor, MI 48109 USA|Univ Michigan, Sch Med, Grad Program Canc Biol, Ann Arbor, MI 48109 USA;

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