title: Cancer-associated oxidoreductase ERO1-α drives the production of tumor-promoting myeloid-derived suppressor cells via oxidative protein folding.
abstract: Endoplasmic reticulum disulfide oxidase ERO1-α plays a role in the formation of disulfide bonds in collaboration with protein disulfide isomerase. Disulfide bond formation is required for the proper conformation and function of secreted and cell surface proteins. We found that ERO1-α was overexpressed in a variety of tumor types; therefore, we examined its role in tumor growth. In BALB/c mice, knockdown of ERO1-α within 4T1 mouse mammary gland cancer (KD) cells caused retardation of in vivo tumor growth compared with tumor growth of scrambled control (SCR) cells. In contrast, when ERO1-α-overexpressed 4T1 (OE) cells were compared with mock control cells, OE cells showed augmented tumor growth. However, differences in tumor growth were not observed among four groups of nude mice, suggesting that expression of ERO1-α diminished antitumor immunity. We observed dense peritumoral granulocytic infiltrates in tumors of wild-type 4T1 and SCR cells but not KD cells, and these cells were identified as polymorphonuclear myeloid-derived suppressor cells (MDSCs). In addition, production of G-CSF and CXCL1/2, which have intramolecular disulfide bonds, from KD cells was significantly decreased compared with that from SCR cells. In contrast, OE cells produced a larger amount of these molecules than did mock cells. These changes were regulated at the posttranscriptional level. These results suggest that overexpression of ERO1-α in the tumor inhibits the T cell response by recruiting polymorphonuclear MDSCs via regulation of MDSC-prone cytokines and chemokines.
authors.affiliation: Department of Pathology, Sapporo Medical University, Sapporo 060-8556, Japan; The United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi 753-8551, Japan;
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Sapporo Medical University, Sapporo 060-8556, Japan;
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Kajiwara
authors.affiliation: Department of Pathology, Sapporo Medical University, Sapporo 060-8556, Japan;
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Torigoe
authors.affiliation: Joint Department of Veterinary Medicine, Tottori University, Tottori 680-8553, Japan; and.
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Okamoto
authors.affiliation: Department of Pathology, Sapporo Medical University, Sapporo 060-8556, Japan;
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Sato
authors.affiliation: Department of Molecular Therapeutics, Center for Food and Medical Innovation, Hokkaido University, Sapporo 001-0021, Japan ytamura3566@gmail.com.
authors.forename: Yasuaki
authors.identifier: http://orcid.org/0000-0002-0112-8730
authors.initials: Y
authors.lastname: Tamura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000276:immunology*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology*; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000276:immunology*; D017510:Protein Folding; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000276:immunology*
chemical_list: D006023:Glycoproteins; D008562:Membrane Glycoproteins; C405327:ERO1A protein, human; C491864:Ero1l protein, mouse; D010088:Oxidoreductases