title: The stress-response sensor chop regulates the function and accumulation of myeloid-derived suppressor cells in tumors.
abstract: Adaptation of malignant cells to the hostile milieu present in tumors is an important determinant of their survival and growth. However, the interaction between tumor-linked stress and antitumor immunity remains poorly characterized. Here, we show the critical role of the cellular stress sensor C/EBP-homologous protein (Chop) in the accumulation and immune inhibitory activity of tumor-infiltrating myeloid-derived suppressor cells (MDSCs). MDSCs lacking Chop had decreased immune-regulatory functions and showed the ability to prime T cell function and induce antitumor responses. Chop expression in MDSCs was induced by tumor-linked reactive oxygen and nitrogen species and regulated by the activating-transcription factor-4. Chop-deficient MDSCs displayed reduced signaling through CCAAT/enhancer-binding protein-β, leading to a decreased production of interleukin-6 (IL-6) and low expression of phospho-STAT3. IL-6 overexpression restored immune-suppressive activity of Chop-deficient MDSCs. These findings suggest the role of Chop in tumor-induced tolerance and the therapeutic potential of targeting Chop in MDSCs for cancer immunotherapy.
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Paul T
authors.initials: PT
authors.lastname: Thevenot
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Rosa A
authors.initials: RA
authors.lastname: Sierra
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Raber
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Amir A
authors.initials: AA
authors.lastname: Al-Khami
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Jimena
authors.initials: J
authors.lastname: Trillo-Tinoco
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Parisa
authors.initials: P
authors.lastname: Zarreii
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Augusto C
authors.initials: AC
authors.lastname: Ochoa
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Del Valle
authors.affiliation: Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA; Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. Electronic address: prodri1@lsuhsc.edu.
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Rodriguez
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology; D009369:Neoplasms; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000276:immunology; D026361:Reactive Nitrogen Species / Q000276:immunology; D017382:Reactive Oxygen Species / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology*; D051742:Transcription Factor CHOP / Q000096:biosynthesis / Q000235:genetics*; D019139:Tumor Escape / Q000276:immunology*
chemical_list: C081452:Atf4 protein, mouse; D022782:CCAAT-Enhancer-Binding Protein-beta; C497250:Ddit3 protein, mouse; D015850:Interleukin-6; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051701:Activating Transcription Factor 4; D051742:Transcription Factor CHOP