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: 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
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 23 Pg. 12331-45 (Dec 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 25514597 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phenylbutyrates
• 4-phenylbutyric acid

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Cell Line, Tumor
• Endoplasmic Reticulum Stress (drug effects, immunology)
• Heterografts
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Myeloid Cells (immunology)
• Neoplasms, Experimental (immunology)
• Phenylbutyrates (pharmacology)
• Real-Time Polymerase Chain Reaction
• Tumor Microenvironment (drug effects, immunology)