Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer.
Many human cancers have been reported to have enhanced expression of the immune checkpoint molecule programmed death-ligand 1 (PD-L1), which binds to programmed cell death-1 (PD-1) expressed on immune cells. PD-L1/PD-1 plays a role in inhibition of antitumor immunity by inducing T cell apoptosis and tolerance. Thus, it is crucial to elucidate mechanisms of PD-L1 expression on cancer cells. ERO1-α is an oxidase located in the endoplasmic reticulum. It is overexpressed in a variety of tumor types and it plays a role in disulfide bond formation in collaboration with PDI. Here, we investigated the influence of ERO1-α on expression of PD-L1 and immune escape. We demonstrated that ERO1-α augmented the expression of PD-L1 via facilitation of oxidative protein folding within PD-L1. In addition, we showed that overexpression of ERO1-α increased HIF-1α protein expression, resulting in an increase of PD-L1 mRNA as well as protein. In clinical cases, we observed that the expression of ERO1-α in triple negative breast cancer was related to the expression of PD-L1. Moreover, apoptosis of Jurkat leukemia T cells, which express PD-1, induced by tumor PD-L1 was inhibited when ERO1-α was depleted. The results suggest that targeting ERO1-α in tumor cells can be a novel approach for cancer immunotherapy. Therefore, the role of ERO1-α in tumor-mediated immunosuppression should be further explored.
Department of Pathology, Sapporo Medical University, Sapporo, Japan.|Department of Clinical Veterinary Medicine, The United Graduate School of Veterinary Sciences, Yamaguchi University, Yamaguchi, Japan.
Tsutomu
T
Tanaka
Department of Surgery, Sapporo Medical University, Sapporo, Japan.
Goro
G
Kutomi
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Toshimitsu
T
Kajiwara
Department of Surgery, Sapporo Medical University, Sapporo, Japan.
Kazuharu
K
Kukita
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Vitaly
V
Kochin
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Takayuki
T
Kanaseki
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Tomohide
T
Tsukahara
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Yoshihiko
Y
Hirohashi
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Toshihiko
T
Torigoe
Joint Department of Veterinary Medicine, Tottori University, Tottori, Japan.
Yoshiharu
Y
Okamoto
Department of Surgery, Sapporo Medical University, Sapporo, Japan.
Koichi
K
Hirata
Department of Pathology, Sapporo Medical University, Sapporo, Japan.
Noriyuki
N
Sato
Department of Molecular Therapeutics, Institute for the Business-Regional Collaboration, Center for Food & Medical Innovation, Hokkaido University, Sapporo, Japan.
Yasuaki
Y
Tamura
D017209:Apoptosis / Q000276:immunology; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000201:enzymology / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D017510:Protein Folding; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000276:immunology; D019139:Tumor Escape; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D008562:Membrane Glycoproteins; D007371:Interferon-gamma; C405327:ERO1A protein, human; D010088:Oxidoreductases
ERO1-α; PD-L1; disulfide bond; oxidoreductase; triple negative breast cancer