Hypoxia augments MHC class I antigen presentation via facilitation of ERO1-α-mediated oxidative folding in murine tumor cells.
To establish an effective cancer immunotherapy, it is crucial that cancer cells present a cancer-specific antigen in a hypoxic area, a hallmark of the tumor microenvironment. Here, we show the impact of hypoxia on MHC class I antigen presentation in vitro and in vivo in murine tumors. Activation of antigen-specific CTLs by tumor cells that had been pre-incubated under a condition of hypoxia was enhanced compared with that by tumor cells pre-incubated under a condition of normoxia. Cell surface expression of MHC class I-peptide complex on the tumor cells was increased under a condition of hypoxia, thereby leading to higher susceptibility to specific CTLs. We show that the hypoxia-inducible ER-resident oxidase ERO1-α plays an important role in the hypoxia-induced augmentation of MHC class I-peptide complex expression. ERO1-α facilitated oxidative folding of MHC class I heavy chains, thereby resulting in the augmentation of cell surface expression of MHC class I-peptide complex under hypoxic conditions. These results suggest that since the expression of MHC class I-peptide complex is augmented in a hypoxic tumor microenvironment, strategies for inhibiting the function of regulatory T cells and myeloid-derived suppressor cells and/or immunotherapy with immune checkpoint inhibitors are promising for improving cancer immunotherapy.
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Toshimitsu
T
Kajiwara
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Tsutomu
T
Tanaka
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Kazuharu
K
Kukita
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Goro
G
Kutomi
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Keita
K
Saito
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Koichi
K
Okuya
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Akari
A
Takaya
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Vitaly
V
Kochin
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Takayuki
T
Kanaseki
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Tomohide
T
Tsukahara
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yoshihiko
Y
Hirohashi
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Toshihiko
T
Torigoe
Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Koichi
K
Hirata
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Noriyuki
N
Sato
Department of Molecular Therapeutics, Center for Food and Medical Innovation, Institute for the Promotion of Business and Regional Collaboration, Hokkaido University, Sapporo, Japan.
Yasuaki
Y
Tamura
D000818:Animals; D017951:Antigen Presentation; D004195:Disease Models, Animal; D005260:Female; D006023:Glycoproteins / Q000378:metabolism*; D006183:H-2 Antigens / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000276:immunology* / Q000628:therapy; D007167:Immunotherapy / Q000379:methods*; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010088:Oxidoreductases; D017510:Protein Folding; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D059016:Tumor Microenvironment
D006023:Glycoproteins; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; C491864:Ero1l protein, mouse; D010088:Oxidoreductases
Cancer immunity; Disulfide bond; Hypoxia; MHC class I molecule; Oxidoreductase