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

Publication ,  Journal Article
Song, M; Sandoval, TA; Chae, C-S; Chopra, S; Tan, C; Rutkowski, MR; Raundhal, M; Chaurio, RA; Payne, KK; Konrad, C; Bettigole, SE; Shin, HR ...
Published in: Nature
October 2018

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.

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Published In

Nature

DOI

EISSN

1476-4687

Publication Date

October 2018

Volume

562

Issue

7727

Start / End Page

423 / 428

Location

England

Related Subject Headings

  • X-Box Binding Protein 1
  • Unfolded Protein Response
  • Tumor Escape
  • T-Lymphocytes
  • Survival Rate
  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Ovarian Neoplasms
  • Neoplasm Transplantation
  • Neoplasm Metastasis
 

Citation

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Song, M., Sandoval, T. A., Chae, C.-S., Chopra, S., Tan, C., Rutkowski, M. R., … Cubillos-Ruiz, J. R. (2018). IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature, 562(7727), 423–428. https://doi.org/10.1038/s41586-018-0597-x
Song, Minkyung, Tito A. Sandoval, Chang-Suk Chae, Sahil Chopra, Chen Tan, Melanie R. Rutkowski, Mahesh Raundhal, et al. “IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.Nature 562, no. 7727 (October 2018): 423–28. https://doi.org/10.1038/s41586-018-0597-x.
Song M, Sandoval TA, Chae C-S, Chopra S, Tan C, Rutkowski MR, et al. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature. 2018 Oct;562(7727):423–8.
Song, Minkyung, et al. “IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity.Nature, vol. 562, no. 7727, Oct. 2018, pp. 423–28. Pubmed, doi:10.1038/s41586-018-0597-x.
Song M, Sandoval TA, Chae C-S, Chopra S, Tan C, Rutkowski MR, Raundhal M, Chaurio RA, Payne KK, Konrad C, Bettigole SE, Shin HR, Crowley MJP, Cerliani JP, Kossenkov AV, Motorykin I, Zhang S, Manfredi G, Zamarin D, Holcomb K, Rodriguez PC, Rabinovich GA, Conejo-Garcia JR, Glimcher LH, Cubillos-Ruiz JR. IRE1α-XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature. 2018 Oct;562(7727):423–428.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

October 2018

Volume

562

Issue

7727

Start / End Page

423 / 428

Location

England

Related Subject Headings

  • X-Box Binding Protein 1
  • Unfolded Protein Response
  • Tumor Escape
  • T-Lymphocytes
  • Survival Rate
  • Signal Transduction
  • Protein Serine-Threonine Kinases
  • Ovarian Neoplasms
  • Neoplasm Transplantation
  • Neoplasm Metastasis