IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity
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 re...
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| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | JOUR |
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| Acceso en línea: | http://hdl.handle.net/20.500.12110/paper_00280836_v562_n7727_p423_Song |
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todo:paper_00280836_v562_n7727_p423_Song |
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dspace |
| institution |
Universidad de Buenos Aires |
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I-28 |
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R-134 |
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Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
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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 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. IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| topic_facet |
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 |
| description |
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. |
| format |
JOUR |
| author |
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. |
| author_facet |
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. |
| author_sort |
Song, M. |
| title |
IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| title_short |
IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| title_full |
IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| title_fullStr |
IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| title_full_unstemmed |
IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity |
| title_sort |
ire1α–xbp1 controls t cell function in ovarian cancer by regulating mitochondrial activity |
| url |
http://hdl.handle.net/20.500.12110/paper_00280836_v562_n7727_p423_Song |
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todo:paper_00280836_v562_n7727_p423_Song2023-10-03T14:38:37Z IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity 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. 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 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00280836_v562_n7727_p423_Song |