IRE1 alpha-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

Article

关键词: ENDOPLASMIC-RETICULUM STRESS;    TUMOR MICROENVIRONMENT;    ER STRESS;    MESSENGER-RNA;    ASCITES;    PROGRESSION;    METABOLISM;    CARCINOMA;    SURVIVAL;    IMMUNITY;   

DOI  :  10.1038/s41586-018-0597-x

来源: SCIE

【 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.

【 授权许可】

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