Cancer-associated oxidoreductase ERO1-α promotes immune escape through up-regulation of PD-L1 in human breast cancer.

Abstract

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.

• Authors: Tsutomu Tanaka, Goro Kutomi, Toshimitsu Kajiwara, Kazuharu Kukita, Vitaly Kochin, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Toshihiko Torigoe, Yoshiharu Okamoto, Koichi Hirata, Noriyuki Sato, Yasuaki Tamura
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 15 Pg. 24706-24718 (Apr 11 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28160557 (Publication Type: Journal Article)

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Membrane Glycoproteins
• Interferon-gamma
• ERO1A protein, human
• Oxidoreductases

Topics

• Apoptosis (immunology)
• B7-H1 Antigen (biosynthesis, immunology)
• Breast Neoplasms (immunology, pathology)
• Cell Line, Tumor
• Female
• Humans
• Interferon-gamma (pharmacology)
• Jurkat Cells
• Leukemia, T-Cell (enzymology, immunology)
• Membrane Glycoproteins (antagonists & inhibitors, biosynthesis, immunology)
• Oxidoreductases (antagonists & inhibitors, biosynthesis, immunology)
• Protein Folding
• Transfection
• Triple Negative Breast Neoplasms (enzymology, immunology)
• Tumor Escape
• Up-Regulation (drug effects, immunology)