Research Papers:

Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells

Bo-Ra Lee _, Sun-Young Chang, Eun-Hye Hong, Bo-Eun Kwon, Hong Min Kim, Yeon-Jeong Kim, Jongkook Lee, Hyun-Jong Cho, Jae-Hee Cheon and Hyun-Jeong Ko

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Oncotarget. 2014; 5:12331-12345. https://doi.org/10.18632/oncotarget.2589

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Bo-Ra Lee1,*, Sun-Young Chang2,*, Eun-Hye Hong1, Bo-Eun Kwon1, Hong Min Kim3, Yeon-Jeong Kim4, Jongkook Lee1, Hyun-Jong Cho1, Jae-Hee Cheon5,#, Hyun-Jeong Ko1,#

1College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea

2College of Pharmacy, Ajou University, Suwon 443-749, Korea

3Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 220-701, Korea

4College of Pharmacy, Inje University, Gimhae 621-749, Korea

5Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-752, Korea

*These authors contributed equally to this work

#Co-senior author

Correspondence to:

Hyun-Jeong Ko, e-mail: [email protected]

Jae Hee Cheon, e-mail: [email protected]

Keywords: cancer, ER stress, MDSC, immunosuppression, arginase-1

Received: August 04, 2014     Accepted: October 11, 2014     Published: December 02, 2014


The role of endoplasmic reticulum (ER) stress in cancer has been studied in detail, and ER stress is known to increase tumor cell apoptosis, and thus, reduce tumor growth. However, in our study, persistent ER stress induced by multiple administrations of low-dose thapsigargin (Tg) accelerated tumor growth in mice. Tg-mediated ER stress increased the generation of Ly6G+CD11b+ myeloid cells, but did not alter anti-tumor effector T cells. 4-Phenylbutyric acid (4-PBA), a chemical chaperone widely used as an ER stress reducer, attenuated Tg-induced myeloid-derived suppressor cell (MDSC) expansion and tumor growth. Tg-mediated ER stress enhanced the immunosuppressive capacity of tumor-infiltrating MDSCs by increasing expression of ARG1, iNOS, and NOX2, although splenic MDSCs were not affected. Consistent with these results, 4-PBA restored the anti-tumor immune response by regulating inflammatory cytokines such as TNF-α and CXCL1/KC, and activated tumor-infiltrating CD8+ T cells that were inhibited by Tg-mediated ER stress. These results suggest that significant ER stress in a tumor-bearing host might induce tumor growth mediated by enhancement of MDSC-mediated suppression. Therefore, ER stress reducers such as 4-PBA could restore anti-tumor immunity by inhibiting suppressive MDSCs that are exacerbated by ER stress.

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