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.
Highlights
Endoplasmic reticulum (ER) stress induction in cancer cells was once a promising strategy for efficiently inducing apoptosis of cancer cells, and several ER stress inducers, including thapsigargin (Tg), a sarcoplasmic/ endoplasmic Ca2+ ATPase inhibitor, were evaluated as anticancer drugs [1]
Figure 6: 4-Phenylbutyric acid (4-PBA) restored anti-tumor immunity via dampening of suppressive myeloidderived suppressor cell (MDSC) exacerbated by ER stress. (A-C) mRNA levels of inflammatory cytokines (IL-6, TNF-α, and KC) from spleen- or tumor-filtrating MDSCs. ns, not significant, *p < 0.05, ***p < 0.001 using one-way ANOVA. (D) the percentage and absolute number of tumor-infiltrating CD4+ T cells (n = 3). (E) the percentage and absolute number of tumor-infiltrating CD8+ T cells (n = 3, one-way ANOVA). (F) surface expression of activation markers CD25 and CD69 in tumor-infiltrating CD4+ T cells (n = 3). (G) surface expression of activation markers CD25 and CD69 in tumorinfiltrating CD8+ T cells (n = 3, one-way ANOVA)
There must be an elevation of ER stress and the unfolded protein response within tumor cells, and tumor-infiltrating cells, including MDSCs, might be under ER stress
Summary
Endoplasmic reticulum (ER) stress induction in cancer cells was once a promising strategy for efficiently inducing apoptosis of cancer cells, and several ER stress inducers, including thapsigargin (Tg), a sarcoplasmic/ endoplasmic Ca2+ ATPase inhibitor, were evaluated as anticancer drugs [1]. Systemic administration of Tg induced non-selective apoptosis of host cells, including proliferative and quiescent cells [2], indicating that Tg might not be a good candidate anticancer drug for systemic administration To overcome this limitation, targeted delivery of Tg has been evaluated in several murine cancer models [1, 3]. Direct induction of apoptotic death in cancer cells may be critical for therapeutic antitumor www.impactjournals.com/oncotarget effects, the tumor antigen-specific immune response against cancer cells has been shown to efficiently inhibit tumor growth and eradicate residual tumor cells In this regard, Tg-induced cell death could beneficially induce tumor-specific immunity following phagocytosis by dendritic cells [1]. We as well as other researchers have provided evidence supporting the combined therapeutic strategy of apoptosis induction by anticancer drugs and activation of the host immune system to remove residual cancer cells [4]
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