Myeloid-Derived Suppressor Cells Suppress Antitumor Immune Responses through IDO Expression and Correlate with Lymph Node Metastasis in Patients with Breast Cancer

Abstract

Myeloid-derived suppressor cells (MDSCs) represent heterogeneous immunosuppressive cells in multiple cancer types and display potent immunosuppressive activity on T cells. We have shown the increased expression of IDO in breast cancer. Because IDO plays a pivotal role in immune tolerance via suppressing T cell function, the aim of this study was to investigate the expression of IDO in MDSCs in breast cancer and its role in MDSC-mediated inhibition of immune surveillance. The proportion of MDSCs with the phenotype of CD45+CD13+CD33+CD14−CD15− significantly increased in primary cancer tissues and patients’ peripheral blood. IDO expression was significantly upregulated in MDSCs isolated from fresh breast cancer tissues (fresh MDSCs [fMDSCs]), which correlated with increased infiltration of Foxp3+ regulatory T cells in tumors and lymph node metastasis in patients. fMDSCs inhibited IL-2 and anti-CD3/CD28 mAb-induced T cell amplification and Th1 polarization but stimulated apoptosis in T cells in an IDO-dependent manner. CD33+ progenitors isolated from healthy donors’ umbilical cord blood were cocultured with breast cancer cell line MDA-MB-231 cells to induce MDSCs. IDO expression was upregulated in induced MDSCs, which required phosphorylation of STAT3, but not STAT1. IDO was required for induced MDSCs’ immunosuppressive activity on T cells, which was blocked by IDO inhibitor 1-methyl-L-tryptophan or STAT3 antagonist JSI-124. Consistently, increased STAT3 phosphorylation level was found in fMDSCs. Together, our findings suggest that STAT3-dependent IDO expression mediates immunosuppressive effects of MDSCs in breast cancer. Thus, inhibition of MDSC-induced T cell suppression by blocking IDO may represent a previously unrecognized mechanism underlying immunotherapy for breast cancer.

COX-2 promotes metastasis in nasopharyngeal carcinoma by mediating interactions between cancer cells and myeloid-derived suppressor cells

“…34,45 Here, our data reveal for the first time that expansion of circulating and tumor-infiltrating MDSC populations in NPC patients is positively correlated with the levels of COX-2 in tumor tissues (P < 0.001). COX-2 derives bioactive PGs, particularly PGE2, which is one of the main proinflammatory factors.…”

“…Many studies have reported that COX-2 expression is usually upregulated in human cancers, including NPC. 34,44,45 COX-2 activity is detected throughout the progression of a premalignant lesion to a metastatic phenotype. Increased expression of COX-2 is associated with angiogenesis, decreased host immunity, enhanced invasion and metastasis in cancers.…”

“…28 Recently, several researchers proposed that PGE2 is indispensable for the induction and maintenance of MDSCs in cancer patients. 21,34,48 In the current study, we first revealed that the induction of T-MDSCs is hampered when COX-2 is suppressed in NPC cells in vitro. Furthermore, our data demonstrate that serum IL-6 levels are correlated with the proportion of circulating MDSCs in NPC patients, and blockade of COX-2 expression inhibits the induction of NPC-mediated T-MDSCs by decreasing the secretion of IL-6 from NPC cells in vitro.…”

“…First, we developed an in vitro short-term co-culture model according to a previous report 34 in which CD33 C myeloid progenitors from healthy donors were co-cultured with TW03 using a transwell system (pore diameter 0. (Fig.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…IDO is also produced by MDSCs, regulatory dendritic cells and TAMs [6,52,125,126]. Silencing of IDO within the tumor using Salmonella typhimurium as a tumor-homing vector to deliver a short-hairpin RNA targeting IDO, allowed tumor infiltration of activated ROS-producing neutrophils and consequent tumor cell death [127].…”