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

Minkyung Song, Tito A. Sandoval, Chang-Suk Chae, Sahil Chopra, Chen Tan, Melanie R. Rutkowski, Mahesh Raundhal, Ricardo A. Chaurio, Kyle K. Payne, Csaba Konrad, Sarah E. Bettigole, Hee Rae Shin, Michael J. P. Crowley, Juan P. Cerliani, Andrew V. Kossenkov, Ievgen Motorykin, Sheng Zhang, Giovanni Manfredi, Dmitriy Zamarin, Kevin Holcomb, Paulo C. Rodriguez, Gabriel A. Rabinovich, Jose R. Conejo-Garcia, Laurie H. Glimcher () and Juan R. Cubillos-Ruiz ()
Additional contact information
Minkyung Song: Weill Cornell Graduate School of Medical Sciences
Tito A. Sandoval: Weill Cornell Medicine
Chang-Suk Chae: Weill Cornell Medicine
Sahil Chopra: Weill Cornell Graduate School of Medical Sciences
Chen Tan: Weill Cornell Medicine
Melanie R. Rutkowski: Immunology and Cancer Biology, University of Virginia
Mahesh Raundhal: Dana-Farber Cancer Institute
Ricardo A. Chaurio: H. Lee Moffitt Cancer Center & Research Institute
Kyle K. Payne: H. Lee Moffitt Cancer Center & Research Institute
Csaba Konrad: Brain and Mind Research Institute, Weill Cornell Medicine
Sarah E. Bettigole: Quentis Therapeutics, Inc
Hee Rae Shin: Quentis Therapeutics, Inc
Michael J. P. Crowley: Weill Cornell Graduate School of Medical Sciences
Juan P. Cerliani: Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Andrew V. Kossenkov: The Wistar Institute
Ievgen Motorykin: Institute of Biotechnology, Cornell University
Sheng Zhang: Institute of Biotechnology, Cornell University
Giovanni Manfredi: Brain and Mind Research Institute, Weill Cornell Medicine
Dmitriy Zamarin: Memorial Sloan Kettering Cancer Center
Kevin Holcomb: Weill Cornell Medicine
Paulo C. Rodriguez: H. Lee Moffitt Cancer Center & Research Institute
Gabriel A. Rabinovich: Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)
Jose R. Conejo-Garcia: H. Lee Moffitt Cancer Center & Research Institute
Laurie H. Glimcher: Dana-Farber Cancer Institute
Juan R. Cubillos-Ruiz: Weill Cornell Graduate School of Medical Sciences

Nature, 2018, vol. 562, issue 7727, 423-428

Abstract: Abstract Tumours evade immune control by creating hostile microenvironments that perturb T cell metabolism and effector function1–4. 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 immunotherapies5–8—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.

Keywords: Ovarian Cancer Ascites; Glutamine Transport; Glutamine Carrier; Anti-tumour Functions; Peritoneal Washing Samples (search for similar items in EconPapers)
Date: 2018
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Citations: View citations in EconPapers (3)

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DOI: 10.1038/s41586-018-0597-x

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