Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast …

J Yu, W Du, F Yan, Y Wang, H Li, S Cao… - The Journal of …, 2013 - journals.aai.org
J Yu, W Du, F Yan, Y Wang, H Li, S Cao, W Yu, C Shen, J Liu, X Ren
The Journal of immunology, 2013journals.aai.org
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+ …
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.
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