Journal Article

IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity

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

2018

Overview

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 IRE1α–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 IRE1α–XBP1 activation that suppressed mitochondrial activity and IFNγ 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 IRE1α–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 IRE1α–XBP1 signalling may help to restore the metabolic fitness and anti-tumour capacity of T cells in cancer hosts. In human and mouse models of ovarian cancer, endoplasmic reticulum stress and the activation of the IRE1α–XBP1 pathway decreases the metabolic fitness of T cells and limits their anti-tumour functions.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/109 / 13/31 / 13/95 / 14/34 / 14/5 / 14/63 / 38/91 / 631/250/2152/1566/1618 / 631/67/580/1884/2323 / Ascites / Cancer / Cell activation / Electron transport / Endoplasmic reticulum / Fitness / Fluids / Gene expression / Genes / Genomes / Glucose / Glutamine / Glycosylation / Humanities and Social Sciences / Hypoxia / Immunity / Immunotherapy / Infiltration / Letter / Lymphocytes / Lymphocytes T / Malignancy / Metabolism / Metastases / Metastasis / Microenvironments / Mitochondria / multidisciplinary / Ovarian cancer / Patients / Protein folding / Proteins / Respiration / Science / Science (multidisciplinary) / Stresses / Transcription / Transcription factors / Tumors / γ-Interferon