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.