Hypoxia augments MHC class I antigen presentation via facilitation of ERO1-α-mediated oxidative folding in murine tumor cells.

Abstract

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.

• Authors: Toshimitsu Kajiwara, Tsutomu Tanaka, Kazuharu Kukita, Goro Kutomi, Keita Saito, Koichi Okuya, Akari Takaya, Vitaly Kochin, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Koichi Hirata, Noriyuki Sato, Yasuaki Tamura
• Journal: European journal of immunology (Eur J Immunol) Vol. 46 Issue 12 Pg. 2842-2851 (12 2016) ISSN: 1521-4141 [Electronic] Germany
• PMID: 27667124 (Publication Type: Journal Article)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Glycoproteins
• H-2 Antigens
• H-2Kb protein, mouse
• Ero1l protein, mouse
• Oxidoreductases

Topics

• Animals
• Antigen Presentation
• Disease Models, Animal
• Female
• Glycoproteins (metabolism)
• H-2 Antigens (metabolism)
• Humans
• Hypoxia (immunology, therapy)
• Immunotherapy (methods)
• Melanoma (immunology, therapy)
• Melanoma, Experimental
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Oxidation-Reduction
• Oxidoreductases
• Protein Folding
• T-Lymphocytes, Cytotoxic (immunology, transplantation)
• Tumor Microenvironment