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

2014; Impact Journals LLC; Volume: 5; Issue: 23 Linguagem: Inglês

10.18632/oncotarget.2589

1949-2553

Bora Lee, Sun-Young Chang, Eun-Hye Hong, Bo-Eun Kwon, Hong Min Kim, Yeon‐Jeong Kim, Jong‐Kook Lee, Hyun‐Jong Cho, Jae Hee Cheon, Hyun‐Jeong Ko,

Autophagy in Disease and Therapy

// Bo-Ra Lee 1, * , Sun-Young Chang 2, * , Eun-Hye Hong 1 , Bo-Eun Kwon 1 , Hong Min Kim 3 , Yeon-Jeong Kim 4 , Jongkook Lee 1 , Hyun-Jong Cho 1 , Jae-Hee Cheon 5, # , Hyun-Jeong Ko 1, # 1 College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea 2 College of Pharmacy, Ajou University, Suwon 443-749, Korea 3 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 220-701, Korea 4 College of Pharmacy, Inje University, Gimhae 621-749, Korea 5 Department 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: hjko@kangwon.ac.kr Jae Hee Cheon, e-mail: geniushee@yuhs.ac Keywords: cancer, ER stress, MDSC, immunosuppression, arginase-1 Received: August 04, 2014 Accepted: October 11, 2014 Published: December 02, 2014 ABSTRACT 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.