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

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