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.