Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1,2,3,4. 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 immunotherapies5,6,7,8—induces endoplasmic reticulum stress and activates the IRE1α–XBP1 arm of the unfolded protein response9,10 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.
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Source Data are provided for Figs. 1–4 and Extended Data Figs. 1–8. The NCBI GEO (Gene Expression Omnibus) accession number for RNA sequencing data reported in this paper is GSE118430. The datasets generated during the current study are available from the corresponding authors upon reasonable request.
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Our research was supported by the Irvington Institute Fellowship Program of the Cancer Research Institute (J.R.C.-R.), the Ann Schreiber Mentored Investigator Award of the Ovarian Cancer Research Fund Alliance (J.R.C.-R.), the Ovarian Cancer Academy Early-Career Investigator Award W81XWH-16-1-0438 of the Department of Defense (J.R.C.-R.), the Stand Up to Cancer Innovative Research Grant SU2C-AACR-IRG-03-16 (J.R.C.-R.), the Jacquie Liggett Fellowship Award of Hearing the Ovarian Cancer Whisper (J.R.C.-R.), Weill Cornell Medicine Funds (J.R.C.-R. and L.H.G.), NIH grant R01CA112663 (L.H.G.) and NIH SIG grant 1S10 OD017992-01 (S.Z.) for the Orbitrap Fusion mass spectrometer. We thank T. Iwawaki at Kanazawa Medical University for sharing the Ern1-floxed mouse strain; J. McCormick for expert assistance with cell sorting; L. Cohen-Gould and J. Jimenez for electron microscopy analysis; G. Zhang, Z. Cheng and T. Su for metabolic tracing experiments; all members of the Weill Cornell Epigenomics Facility for assistance with RNA sequencing, T. Walther for help collecting patient samples; J. M. Pérez-Sáez and J. Trillo-Tinoco for assistance with some experimental analyses and helpful suggestions; and L. Cantley and M. Goncalves for sharing valuable instruments and resources. We also thank all members of the Cubillos-Ruiz, Morales and Glimcher laboratories for helpful suggestions and critical reading of this manuscript.
Nature thanks T. Curiel and the other anonymous reviewer(s) for their contribution to the peer review of this work.