Noncanonical NF-κB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer.
Noncanonical NF-κB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer.
复制标题
非规范的NF-κB激活介导了髓样衍生的抑制细胞中STAT3刺激的IDO上调。
DOI：
10.4049/jimmunol.1400833
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发表时间：
2014-09-01
期刊：
影响因子：
--
通讯作者：
Ren X
中科院分区：
文献类型：
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作者：
Yu J;Wang Y;Yan F;Zhang P;Li H;Zhao H;Yan C;Yan F;Ren X
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.
