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Song, M.; Sandoval, T.A.; Chae, C.-S.; Chopra, S.; Tan, C.; Rutkowski, M.R.; Raundhal, M.; Chaurio, R.A.; Payne, K.K.; Konrad, C.; Bettigole, S.E.; Shin, H.R.; Crowley, M.J.P.; Cerliani, J.P.; Kossenkov, A.V.; Motorykin, I.; Zhang, S.; Manfredi, G. (...) Cubillos-Ruiz, J.R. "IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity" (2018) Nature. 562(7727):423-428
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Abstract:

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. © 2018, Springer Nature Limited.

Registro:

Documento: Artículo
Título:IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity
Autor:Song, M.; Sandoval, T.A.; Chae, C.-S.; Chopra, S.; Tan, C.; Rutkowski, M.R.; Raundhal, M.; Chaurio, R.A.; Payne, K.K.; Konrad, C.; Bettigole, S.E.; Shin, H.R.; Crowley, M.J.P.; Cerliani, J.P.; Kossenkov, A.V.; Motorykin, I.; Zhang, S.; Manfredi, G.; Zamarin, D.; Holcomb, K.; Rodriguez, P.C.; Rabinovich, G.A.; Conejo-Garcia, J.R.; Glimcher, L.H.; Cubillos-Ruiz, J.R.
Filiación:Weill Cornell Graduate School of Medical Sciences, New York, NY, United States
Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, United States
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States
Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, United States
Department of Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, United States
Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States
Quentis Therapeutics, Inc, New York, NY, United States
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA, United States
Proteomics & Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, NY, United States
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:gamma interferon; glutamine; messenger RNA; protein IRE1; protein IRE1alpha; unclassified drug; X box binding protein 1; amino acid transporter; ERN1 protein, human; gamma interferon; glucose; glutamine; IFNG protein, human; protein serine threonine kinase; ribonuclease; X box binding protein 1; XBP1 protein, human; animal cell; animal model; animal tissue; ascites fluid; ascites tumor; CD4+ T lymphocyte; controlled study; cytokine production; down regulation; endoplasmic reticulum stress; female; gene expression regulation; glucose transport; human; human cell; human tissue; IFNG gee; Letter; lymphocyte function; lymphocytic infiltration; mitochondrial respiration; mouse; nonhuman; ovary cancer; priority journal; protein glycosylation; signal transduction; transcriptomics; upregulation; animal; ascites; biosynthesis; cancer transplantation; cell respiration; cytology; deficiency; disease exacerbation; genetics; glycosylation; immunology; metabolism; metastasis; mitochondrion; ovary tumor; pathology; survival rate; T lymphocyte; tumor escape; unfolded protein response; Mus; Amino Acid Transport Systems, Basic; Animals; Ascites; Cell Respiration; Disease Progression; Endoplasmic Reticulum Stress; Endoribonucleases; Female; Gene Expression Regulation, Neoplastic; Glucose; Glutamine; Glycosylation; Humans; Interferon-gamma; Mice; Mitochondria; Neoplasm Metastasis; Neoplasm Transplantation; Ovarian Neoplasms; Protein-Serine-Threonine Kinases; Signal Transduction; Survival Rate; T-Lymphocytes; Tumor Escape; Unfolded Protein Response; X-Box Binding Protein 1
Año:2018
Volumen:562
Número:7727
Página de inicio:423
Página de fin:428
DOI: http://dx.doi.org/10.1038/s41586-018-0597-x
Título revista:Nature
Título revista abreviado:Nature
ISSN:00280836
CODEN:NATUA
CAS:gamma interferon, 82115-62-6; glutamine, 56-85-9, 6899-04-3; glucose, 50-99-7, 84778-64-3; protein serine threonine kinase; ribonuclease, 59794-03-5, 9001-99-4; Amino Acid Transport Systems, Basic; Endoribonucleases; ERN1 protein, human; Glucose; Glutamine; IFNG protein, human; Interferon-gamma; Protein-Serine-Threonine Kinases; X-Box Binding Protein 1; XBP1 protein, human
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00280836_v562_n7727_p423_Song

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Citas:

---------- APA ----------
Song, M., Sandoval, T.A., Chae, C.-S., Chopra, S., Tan, C., Rutkowski, M.R., Raundhal, M.,..., Cubillos-Ruiz, J.R. (2018) . IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature, 562(7727), 423-428.
http://dx.doi.org/10.1038/s41586-018-0597-x
---------- CHICAGO ----------
Song, M., Sandoval, T.A., Chae, C.-S., Chopra, S., Tan, C., Rutkowski, M.R., et al. "IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity" . Nature 562, no. 7727 (2018) : 423-428.
http://dx.doi.org/10.1038/s41586-018-0597-x
---------- MLA ----------
Song, M., Sandoval, T.A., Chae, C.-S., Chopra, S., Tan, C., Rutkowski, M.R., et al. "IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity" . Nature, vol. 562, no. 7727, 2018, pp. 423-428.
http://dx.doi.org/10.1038/s41586-018-0597-x
---------- VANCOUVER ----------
Song, M., Sandoval, T.A., Chae, C.-S., Chopra, S., Tan, C., Rutkowski, M.R., et al. IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity. Nature. 2018;562(7727):423-428.
http://dx.doi.org/10.1038/s41586-018-0597-x