Noncanonical NF-κB Activation Mediates STAT3-Stimulated IDO Upregulation in Myeloid-Derived Suppressor Cells in Breast Cancer

作者：Yu, Jinpu; Wang, Yue; Yan, Fang; Zhang, Peng; Li, Hui; Zhao, Hua; Yan, Cihui; Yan, Fan; Ren, Xiubao^*

来源：The Journal of Immunology, 2014, 193(5): 2574-2586.

DOI：10.4049/jimmunol.1400833

• DENDRITIC CELLS
• INDOLEAMINE 2,3-DIOXYGENASE
• SYNERGISTIC INDUCTION
• STAT3 ACTIVATION
• LUNG-CANCER
• IFN-GAMMA
• TNF-ALPHA
• IKK-ALPHA
• EXPRESSION
• PROLIFERATION

Immunotherapy for cancer treatment is achieved through the activation of competent immune effector cells and the inhibition of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs). Although MDSCs have been shown to contribute to breast cancer development, the mechanism underlying MDSC-mediated immunosuppression is unclear. We have identified a poorly differentiated MDSC subset in breast cancer-suppressing T cell function through STAT3-dependent IDO upregulation. In this study we investigated the mechanisms underlying aberrant expression of IDO in MDSCs. MDSCs were induced by coculturing human CD33(+) myeloid progenitors with MDA-MB-231 breast cancer cells. Increased STAT3 activation in MDSCs was correlated with activation of the noncanonical NF-kappa B pathway, including increased NF-kappa B-inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-kappa B kinase alpha and p100, and RelB-p52 nuclear translocation. Blocking STAT3 activation with the small molecule inhibitor JSI-124 significantly inhibited the accumulation of NIK and IDO expression in MDSCs. Knockdown of NIK in MDSCs suppressed IDO expression but not STAT3 activation. RelB-p52 dimers were found to directly bind to the IDO promoter, leading to IDO expression in MDSCs. IL-6 was found to stimulate STAT3-dependent, NF-kappa B-mediated IDO upregulation in MDSCs. Furthermore, significant positive correlation between the numbers of pSTAT3(+) MDSCs, IDO+ MDSCs, and NIK+ MDSCs was observed in human breast cancers. These results demonstrate a STAT3/NF-kappa B/IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer.

• 出版日期2014-9-1
• 单位天津医科大学