Abstract 2353: Noncanonical NF-κB activation mediates STAT3-stimulated IDO up-regulation in myeloid-derived suppressor cells in breast cancer

Abstract

Abstract 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). While MDSCs have been shown to contribute to breast cancer development, the mechanism underlying MDSCs-mediated immunosuppression is unclear. We have identified a poorly differentiated MDSC subset in breast cancer suppressing T-cell function through signal transducer and activator of transcription (STAT) 3-dependent indoleamine 2,3 dioxygenase (IDO) up-regulation. Here we investigated the mechanisms underlying aberrant expression of IDO in MDSCs. MDSCs were induced by co-culturing human CD33+ myeloid progenitors with MDA-MB-231 breast cancer cells. Increased STAT3 activation in MDSCs was correlated with activation of the noncanonical nuclear factor-κB (NF-κB) pathway, including increased NF-κB-inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-κB kinase (IKK) α 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. Knock-down 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-κB-mediated IDO up-regulation 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-κB-IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer. Citation Format: Jinpu Yu, Yue Wang, Hui Li, Xiubao Ren. Noncanonical NF-κB activation mediates STAT3-stimulated IDO up-regulation in myeloid-derived suppressor cells in breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2353. doi:10.1158/1538-7445.AM2015-2353