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

Song, Minkyung; Sandoval, Tito A.; Chae, Chang-Suk; Chopra, Sahil; Tan, Chen; Rutkowski, Melanie R.; Raundhal, Mahesh; Chaurio, Ricardo A.; Payne, Kyle K.; Konràd, Csaba; Bettigole, Sarah E.; Shin, Hee Rae; Crowley, Michael J.; Cerliani, Juan P.; Kossenkov, Andrew V.; Motorykin, Ievgen; Zhang, Sheng; Manfredi, Giovanni; Zamarin, Dmitriy; Holcomb, Kevin; Rodríguez, Paulo C.; Rabinovich, Gabriel A.; Conejo-Garcia, José R.; Glimcher, Laurie H.; Cubillos-Ruiz, Juan R.

doi:10.1038/s41586-018-0597-x

Cited by 283 publications

(266 citation statements)

References 41 publications

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“…We crossed the CHOP KO and IL-24 KO strains to produce the double knockout (DKO) strain. The Xbp1 F/F strain, a gift from Dana Farber Cancer Institute, USA, was previously described [36]. Mice devoid of XBP1 selectively in hepatocytes were generated by breeding the Xbp1 F/F mice with Alb Cre strain.…”

Section: Methodsmentioning

confidence: 99%

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Wang

Zhao

et al. 2019

Preprint

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Endoplasmic reticulum (ER) stress-associated cell death is prevalent in various liver diseases. However, the determinant mechanism how hepatocytes survive unresolved stress was still unclear. Interleukin-24 (IL-24) was previously found to promote ER stress-mediated cell death, and yet its expression and function in the liver remained elusive. Here we identified an anti-apoptotic role of IL-24, which transiently accumulated within ER-stressed hepatocytes in a X-box binding protein 1 (XBP1)-dependent manner. Disruption of IL-24 increased cell death in the CCL4- or APAP-challenged mouse liver or Tm-treated hepatocytes. In contrast, pharmaceutical blockade of eukaryotic initiation factor 2α (eIF2α) or genetical ablation of C/EBP homologous protein (CHOP) restored hepatocyte function in the absence of IL-24. In a clinical setting, patients with acute liver failure manifested a profound decrease of hepatic IL-24 expression, which was associated with disease progression. In conclusion, intrinsic hepatocyte IL-24 maintains ER homeostasis by restricting the eIF2α-CHOP pathway-mediated stress signal, which might be exploited as a bio-index for prognosis or therapeutic intervention in patients with liver injury.

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Section: Methodsmentioning

confidence: 99%

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Wang

Zhao

et al. 2019

Preprint

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“…The IRE1α-XBP1 pathway in CD4 + T cells has also been implicated in antitumor immunity in ovarian cancer. Mechanistically, the induction of XBP1s limits the influx of glutamine, which is necessary for sustaining mitochondrial respiration in CD4 + T cells under glucose-deprived conditions which reflects TME (100). Aside from the roles of UPR in effector T-cell differentiation and function, ER stress also regulates Tcell autophagy and apoptosis.…”

Section: Cd4 + T Cellsmentioning

confidence: 99%

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Song

Riesenberg

et al. 2020

Front. Immunol.

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The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.Frontiers in Immunology | www.frontiersin.org Conflict of Interest: ZL serves as member of scientific advisory board for Alphamab and Henlius Biotech and has a sponsored research agreement with Bristol-Myers Squibb.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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“…3e). The first inflection point (pseudotime 0. has been shown to control T cell function and mitochondrial activity 66 . Further, we observed reduced expression of carnitine palmitoyltransferase (CPT1A), a rate-limiting enzyme of fatty acid oxidation.…”

Section: Integrative Modeling Of T Cell Activation Identifies Checkpomentioning

confidence: 99%

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

Hartmann

Mrdjen

McCaffrey

et al. 2020

Preprint

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Cellular metabolism regulates immune cell activation, differentiation and effector functions to the extent that its perturbation can augment immune responses. However, the analytical technologies available to study cellular metabolism lack single-cell resolution, obscuring metabolic heterogeneity and its connection to immune phenotype and function. To that end, we utilized high-dimensional, antibody-based technologies to simultaneously quantify the single-cell metabolic regulome in combination with phenotypic identity. Mass cytometry (CyTOF)-based application of this approach to early human T cell activation enabled the comprehensive reconstruction of the coordinated metabolic remodeling of naïve CD8 + T cells and aligned with conventional bulk assays for glycolysis and oxidative phosphorylation. Extending this analysis to a variety of tissue-resident immune cells revealed tissue-restricted metabolic states of human cytotoxic T cells, including metabolically repressed subsets that expressed CD39 and PD1 and that were enriched in colorectal carcinoma versus healthy adjacent tissue. Finally, combining this approach with multiplexed ion beam imaging by time-of-flight (MIBI-TOF) demonstrated the existence of spatially enriched metabolic neighborhoods, independent of cell identity and additionally revealed exclusion of metabolically repressed cytotoxic T cell states from the tumor-immune boundary in human colorectal carcinoma. Overall, we provide an approach that permits the robust approximation of metabolic states in individual cells along with multimodal analysis of cell identity and functional characteristics that can be applied to human clinical samples to study cellular metabolism how it may be perturbed to affect immunological outcomes.

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

Cited by 283 publications

References 41 publications

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

Intracellular XBP1-IL-24 axis dismantles cytotoxic unfolded protein response in the liver

The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities

Multiplexed Single-cell Metabolic Profiles Organize the Spectrum of Cytotoxic Human T Cells

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