Immunotherapy exerts anticancer effects by activating competent immune effectors and inhibiting immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). However, the mechanism underlying MDSCs-mediated immunosuppression in breast cancer is unclear. We have identified a poorly differentiated subset of MDSCs in breast cancer, which suppresses T-cell functions through STAT3-dependent IDO upregulation. Here, we aimed to investigate the mechanisms by which IDO expression is aberrant in MDSCs. We found increased STAT3 phosphorylation and NIK expression were correlated with upregulated IDO expression in MDSCs in human breast cancer. In mouse 4T1 mammary cancer model, blocking STAT3 signal significantly inhibited the activation of NF-κB and IDO expression in MDSCs, resulting in decrease of tumor growth and metastasis. We also induced MDSCs by co-culturing human CD33+ myeloid progenitors with MDA-MB-231 breast cancer cells. In these induced MDSCs, increased STAT3 activation was correlated with the activation of the noncanonical NF-κB pathway, including increased NIK protein level, phosphorylation of IKKα and p100 in cytoplasm, and RelB-p52 nuclear translocation. Blocking STAT3 activation significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knock-down of NIK by siRNA transfection in MDSCs suppressed IDO expression, but not STAT3 activation. Transcription factor assay and ChIP assay showed that RelB-p52 dimers directly bound to the IDO promoter, leading to IDO expression in MDSCs. These results suggest a STAT3-NF-κB-IDO pathway in breast cancer-derived MDSCs. Furthermore, IL-6 was found to stimulate STAT3-dependent NF-κB-mediated IDO upregulation in MDSCs. This study provides insights into understanding mechanisms through which MDSCs play an immunosuppressive role in breast cancer.

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CD4(+)FoxP3(+) regulatory T cells (Tregs) represent a major cellular mediator of cancer immune evasion. The expression of tumor necrosis factor receptor type II (TNFR2) on Tregs is reported to identify the maximally suppressive Treg population in both mice and human. We therefore investigated the phenotype and function of TNFR2(+) Tregs present in the peripheral blood (PB) of 43 lung cancer patients. Further, the association of TNFR2 expression on Tregs with clinicopathological factors was analyzed. The results showed that in the PB of lung cancer patients, Tregs expressed markedly higher levels of TNFR2 than conventional T cells (Tconvs). Expression of TNFR2 appeared to correlate better than CD25(+) and CD127(-) with FoxP3 expression. PB TNFR2(+) Tregs in lung cancer patients were more proliferative and expressed higher levels of the immunosuppressive molecule CTLA-4, and consequently more potently suppressed IFNγ production by cocultured CD8 CTLs. More importantly, higher TNFR2 expression levels on Tregs were associated with lymphatic invasion, distant metastasis and more advanced clinical stage of lung cancer patients. Therefore, our study suggests that TNFR2(+) Tregs play a role in promoting tumor progressive metastasis and expression of TNFR2 by PB Tregs may prove to be a useful prognostic marker in lung cancer patients.