title: Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells.
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.
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Bo-Ra
authors.initials: BR
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Ajou University, Suwon 443-749, Korea.
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Chang
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Eun-Hye
authors.initials: EH
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Bo-Eun
authors.initials: BE
authors.lastname: Kwon
authors.affiliation: Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju 220-701, Korea.
authors.forename: Hong Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Inje University, Gimhae 621-749, Korea.
authors.forename: Yeon-Jeong
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Jongkook
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Hyun-Jong
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul 120-752, Korea.
authors.forename: Jae-Hee
authors.initials: JH
authors.lastname: Cheon
authors.affiliation: College of Pharmacy, Kangwon National University, Chuncheon 200-701, Korea.
authors.forename: Hyun-Jeong
authors.initials: HJ
authors.lastname: Ko
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000276:immunology*; D064593:Heterografts; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid