title: Noncanonical NF-κB activation mediates STAT3-stimulated IDO upregulation in myeloid-derived suppressor cells in breast cancer.
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). 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-κB pathway, including increased NF-κB-inducing kinase (NIK) protein level, phosphorylation of cytoplasmic inhibitor of NF-κB kinase 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. 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-κB-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-κB/IDO pathway in breast cancer-derived MDSCs, which provides insight into understanding immunosuppressive mechanisms of MDSCs in breast cancer.
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; rwziyi@yahoo.com yujinpu@tjmuch.com.
authors: Jinpu
authors: J
authors: Yu
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors: Yue
authors: Y
authors: Wang
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, TN 37232; and.
authors: Fang
authors: F
authors: Yan
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors: Peng
authors: P
authors: Zhang
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors: Hui
authors: H
authors: Li
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors: Hua
authors: H
authors: Zhao
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors: Cihui
authors: C
authors: Yan
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China;
authors: Fan
authors: F
authors: Yan
authors: Department of Immunology, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China; Biotherapy Center, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, People's Republic of China rwziyi@yahoo.com yujinpu@tjmuch.com.
authors: Xiubao
authors: X
authors: Ren
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002467:Cell Nucleus / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D051841:Transcription Factor RelB / Q000235:genetics / Q000276:immunology*; D014315:Triterpenes / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015850:Interleukin-6; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D050796:STAT3 Transcription Factor; D051841:Transcription Factor RelB; D014315:Triterpenes; D000097782:NF-kappaB-Inducing Kinase; C576710:IDO1 protein, human; C508600:IL6 protein, human; C497593:RELB protein, human; C494086:STAT3 protein, human; C038106:cucurbitacin I