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

Autor: Ievgen Motorykin, Sheng Zhang, Tito A. Sandoval, Sahil Chopra, Csaba Konrad, Melanie R. Rutkowski, Gabriel A. Rabinovich, Mahesh Raundhal, Minkyung Song, Kevin Holcomb, Paulo C. Rodriguez, Chang-Suk Chae, Jose R. Conejo-Garcia, Dmitriy Zamarin, Laurie H. Glimcher, Michael J. Crowley, Andrew V. Kossenkov, Sarah E. Bettigole, Hee Rae Shin, Giovanni Manfredi, Juan R. Cubillos-Ruiz, Kyle K. Payne, Chen Tan, Ricardo A. Chaurio, Juan P. Cerliani
Rok vydání: 2017
Předmět:
0301 basic medicine
X-Box Binding Protein 1
Glycosylation
Glutamine
T-Lymphocytes
Mitochondrion
Glutamine transport
purl.org/becyt/ford/1 [https]
Mice
Neoplasm Metastasis
Ovarian Neoplasms
Multidisciplinary
Otras Medicina Básica
Ascites
purl.org/becyt/ford/3.1 [https]
Endoplasmic Reticulum Stress
OVARIAN CANCER
3. Good health
XBP1
Mitochondria
Gene Expression Regulation
Neoplastic
Survival Rate
Medicina Básica
medicine.anatomical_structure
Disease Progression
purl.org/becyt/ford/3 [https]
Female
CIENCIAS NATURALES Y EXACTAS
Signal Transduction
CIENCIAS MÉDICAS Y DE LA SALUD
T cell
Otras Ciencias Biológicas
Cell Respiration
Inmunología
IRE1
Biology
Protein Serine-Threonine Kinases
Ciencias Biológicas
03 medical and health sciences
Interferon-gamma
Downregulation and upregulation
Endoribonucleases
medicine
Animals
Humans
purl.org/becyt/ford/1.6 [https]
Endoplasmic reticulum
T CELL
medicine.disease
030104 developmental biology
Glucose
Unfolded protein response
Cancer research
Unfolded Protein Response
Amino Acid Transport Systems
Basic
Tumor Escape
Ovarian cancer
Neoplasm Transplantation
Zdroj: CONICET Digital (CONICET)
Consejo Nacional de Investigaciones Científicas y Técnicas
instacron:CONICET
ISSN: 1476-4687
Popis: 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. Fil: Song, Minkyung. Weill Cornell Medicine; Estados Unidos Fil: Sandoval, Tito A.. Weill Cornell Medicine; Estados Unidos Fil: Chae, Chang-Suk. Weill Cornell Medicine; Estados Unidos Fil: Chopra, Sahil. Weill Cornell Medicine; Estados Unidos Fil: Tan, Chen. Weill Cornell Medicine; Estados Unidos Fil: Rutkowski, Melanie R.. University of Virginia; Estados Unidos Fil: Raundhal, Mahesh. Dana Farber Cancer Institute; Estados Unidos. Harvard Medical School; Estados Unidos Fil: Chaurio, Ricardo A.. H. Lee Moffitt Cancer Center & Research Institute; Estados Unidos Fil: Payne, Kyle K.. H. Lee Moffitt Cancer Center & Research Institute; Estados Unidos Fil: Konrad, Csaba. Weill Cornell Medicine; Estados Unidos Fil: Bettigole, Sarah E.. Quentis Therapeutics Inc.; Estados Unidos Fil: Shin, Hee Rae. Quentis Therapeutics Inc.; Estados Unidos Fil: Crowley, Michael J. P.. Weill Cornell Graduate School of Medical Sciences; Estados Unidos Fil: Cerliani, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Kossenkov, Andrew V.. The Wistar Institute; Estados Unidos Fil: Motorykin, Ievgen. Weill Cornell Medicine,; Estados Unidos Fil: Zhang, Sheng. Weill Cornell Medicine,; Estados Unidos Fil: Manfredi, Giovanni. Weill Cornell Medicine,; Estados Unidos Fil: Zamarin, Dmitriy. Memorial Sloan Kettering Cancer Center; Estados Unidos Fil: Holcomb, Kevin. Weill Cornell Medicine,; Estados Unidos Fil: Rodriguez, Paulo C.. H. Lee Moffitt Cancer Center & Research Institute; Estados Unidos Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Conejo Garcia, Jose R.. H. Lee Moffitt Cancer Center & Research Institute; Estados Unidos Fil: Glimcher, Laurie H.. Dana Farber Cancer Institute; Estados Unidos. Harvard Medical School; Estados Unidos Fil: Cubillos-Ruiz, Juan R.. Weill Graduate School Of Medical Sciences; Estados Unidos. Weill Graduate School Of Medical Sciences; Estados Unidos
Databáze: OpenAIRE
Externí odkaz: