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, Hyun Jeong Ko

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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 myeloidderived 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-a and CXCL1/KC, and activated tumorinfiltrating 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.

Original languageEnglish
Pages (from-to)12331-12345
Number of pages15
JournalOncotarget
Volume5
Issue number23
DOIs
Publication statusPublished - 2014 Jan 1

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Lee, B. R., Chang, S. Y., Hong, E. H., Kwon, B. E., Kim, H. M., Kim, Y. J., Lee, J., Cho, H. J., Cheon, J. H., & Ko, H. J. (2014). Elevated endoplasmic reticulum stress reinforced immunosuppression in the tumor microenvironment via myeloid-derived suppressor cells. Oncotarget, 5(23), 12331-12345. https://doi.org/10.18632/oncotarget.2589