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首页> 外文期刊>Nature >IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity
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IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

机译：IRE1α-XBP1通过调节线粒体活性来控制卵巢癌T细胞功能

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摘要

Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function(1-4). However, it remains unclear how intra-tumoral T cells integrate and interpret metabolic stress signals. Here we report that ovarian cancer-an aggressive malignancy that is refractory to standard treatments and current immunotherapies(5-8)-induces endoplasmic reticulum stress and activates the IRE1 alpha-XBP1 arm of the unfolded protein response(9,10) in T cells to control their mitochondrial respiration and anti-tumour function. In T cells isolated from specimens collected from patients with ovarian cancer, upregulation of XBP1 was associated with decreased infiltration of T cells into tumours and with reduced IFNG mRNA expression. Malignant ascites fluid obtained from patients with ovarian cancer inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, which triggered IRE1 alpha-XBP1 activation that suppressed mitochondrial activity and IFN-gamma production. Mechanistically, induction of XBP1 regulated the abundance of glutamine carriers and thus limited the influx of glutamine that is necessary to sustain mitochondrial respiration in T cells under glucose-deprived conditions. Restoring N-linked protein glycosylation, abrogating IRE1 alpha-XBP1 activation or enforcing expression of glutamine transporters enhanced mitochondrial respiration in human T cells exposed to ovarian cancer ascites. XBP1-deficient T cells in the metastatic ovarian cancer milieu exhibited global transcriptional reprogramming and improved effector capacity. Accordingly, mice that bear ovarian cancer and lack XBP1 selectively in T cells demonstrate superior anti-tumour immunity, delayed malignant progression and increased overall survival. Controlling endoplasmic reticulum stress or targeting IRE1 alpha-XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts.
机译：肿瘤通过产生不利于扰动T细胞代谢和效应功能的微环境来逃避免疫控制（1-4）。然而，尚不清楚肿瘤内T细胞如何整合和解释代谢应激信号。在这里我们报道卵巢癌-一种侵袭性恶性肿瘤，对标准治疗和当前的免疫疗法是难治性的（5-8）-诱导内质网应激并激活IRE1 alpha-XBP1臂在T细胞中未折叠的蛋白反应（9,10）以控制其线粒体呼吸和抗肿瘤功能。在从卵巢癌患者的标本中分离的T细胞中，XBP1的上调与T细胞浸润到肿瘤中的减少以及IFNG mRNA表达的降低有关。从卵巢癌患者获得的恶性腹水抑制葡萄糖摄取，并引起T细胞中N-联蛋白糖基化缺陷，从而触发IRE1 alpha-XBP1活化，从而抑制线粒体活性和IFN-γ产生。从机制上讲，XBP1的诱导调节了谷氨酰胺载体的丰度，因此限制了在葡萄糖缺乏条件下维持T细胞线粒体呼吸所必需的谷氨酰胺的流入。恢复N-连锁蛋白糖基化，消除IRE1 alpha-XBP1激活或增强谷氨酰胺转运蛋白的表达可增强暴露于卵巢癌腹水的人T细胞的线粒体呼吸作用。转移性卵巢癌环境中的XBP1缺陷T细胞表现出整体转录重编程和提高的效应器能力。因此，患有卵巢癌且在T细胞中选择性缺乏XBP1的小鼠表现出优异的抗肿瘤免疫力，延迟的恶性进展和增加的总生存期。控制内质网应激或靶向IRE1α-XBP1信号传导可能有助于恢复癌症宿主中T细胞的代谢适应性和抗肿瘤能力。

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  • 来源
    《Nature》 |2018年第7727期|423-428|共6页
  • 作者

    Song Minkyung; Sandoval Tito A.; Chae Chang-Suk; Chopra Sahil; Tan Chen; Rutkowski Melanie R.; Raundhal Mahesh; Chaurio Ricardo A.; Payne Kyle K.; Konrad Csaba; Bettigole Sarah E.; Shin Hee Rae; Crowley Michael J. P.; Cerliani Juan P.; Kossenkov Andrew V.; Motorykin Ievgen; Zhang Sheng; Manfredi Giovanni; Zamarin Dmitriy; Holcomb Kevin; Rodriguez Paulo C.; Rabinovich Gabriel A.; Conejo-Garcia Jose R.; Glimcher Laurie H.; Cubillos-Ruiz Juan R.;

  • 作者单位

    Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA;

    Weill Cornell Med, Dept Obstet & Gynecol, New York, NY 10065 USA;

    Weill Cornell Med, Dept Obstet & Gynecol, New York, NY 10065 USA;

    Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA;

    Weill Cornell Med, Dept Obstet & Gynecol, New York, NY 10065 USA;

    Univ Virginia, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA USA;

    Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA;

    H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA;

    H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA;

    Weill Cornell Med, Brain & Mind Res Inst, New York, NY USA;

    Quentis Therapeut Inc, New York, NY USA;

    Quentis Therapeut Inc, New York, NY USA;

    Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA;

    Consejo Nacl Invest Cient & Tecn, IBYME, Lab Inmunopatol, Buenos Aires, DF, Argentina;

    Wistar Inst Anat & Biol, Ctr Syst & Computat Biol, 3601 Spruce St, Philadelphia, PA 19104 USA;

    Cornell Univ, Prote & Mass Spectrometry Facil, Inst Biotechnol, Ithaca, NY USA;

    Cornell Univ, Prote & Mass Spectrometry Facil, Inst Biotechnol, Ithaca, NY USA;

    Weill Cornell Med, Brain & Mind Res Inst, New York, NY USA;

    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA;

    Weill Cornell Med, Dept Obstet & Gynecol, New York, NY 10065 USA;

    H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA;

    Consejo Nacl Invest Cient & Tecn, IBYME, Lab Inmunopatol, Buenos Aires, DF, Argentina;

    H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL USA;

    Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA;

    Weill Cornell Grad Sch Med Sci, New York, NY 10065 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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