title: Bortezomib Relieves Immune Tolerance in Nasopharyngeal Carcinoma via STAT1 Suppression and Indoleamine 2,3-Dioxygenase Downregulation.
abstract: Radiotherapy is the primary treatment for nasopharyngeal carcinoma (NPC). Patients with intermediate and advanced stage NPC receiving only radiotherapy have limited survival, so newer immunotherapeutic approaches are sought. The major impediment to better clinical outcomes is tumor immune tolerance. Indoleamine 2,3-dioxygenase (IDO), an IFNγ-inducible enzyme, is a major inducer of immune tolerance during tumor development; therefore, inhibition of the IDO pathway is an important modality for cancer treatment. We show that bortezomib, a proteasomal inhibitor, inhibited the pathways leading to STAT1 and IRF-1 activation, both of which are necessary for IDO expression. Bortezomib downregulated IFNγ-induced IDO expression via inhibition of STAT1 phosphorylation and nuclear translocation, thereby suppressing STAT1-driven IDO transcription in NPC cells. Bortezomib also promoted IκB-α phosphorylation-ubiquitination, which released NF-κB from IκB-α. However, the released NF-κB could not enter the nucleus to conduct its biological effects and accumulated in the cytoplasm. Negative feedback inhibited the transcription of NF-κB, which is important for activating IRF-1 expression. IDO expression is regulated by two important transcription factor binding sites, ISREs, which bind STAT1 and IRF-1, and GASs, which binds STAT1. Bortezomib upregulated IRF-1 protein by inhibiting its proteasome-dependent degradation, but it also inhibited STAT1 phosphorylation, which directly inhibited the activation of GAS and indirectly inhibited the activation of ISRE, which needs both STAT1 and IRF-1. These discoveries provide a mechanism for the antitumor action of bortezomib and have implications for the development of clinical cancer immunotherapy for preventing and treating NPC. Cancer Immunol Res; 5(1); 42-51. ©2016 AACR.
authors.affiliation: Department of Clinical Laboratory, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. jiangguanmin@hnszlyy.com whongsh@mail.sysu.edu.cn liangjianping@hnszlyy.com.
authors.forename: Guan-Min
authors.initials: GM
authors.lastname: Jiang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China. jiangguanmin@hnszlyy.com whongsh@mail.sysu.edu.cn liangjianping@hnszlyy.com.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Wang
authors.affiliation: Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Microbiology, School of Public Health and Tropical Medicine, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Wei-Feng
authors.initials: WF
authors.lastname: Ma
authors.affiliation: Key Laboratory of Translational Radiation Oncology, Hunan Province, Changsha, Hunan, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of ICU, Hunan Children's Hospital, Changsha, Hunan, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
authors.forename: Qiu-Gui
authors.initials: QG
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Clinical Laboratory, The First Affiliated Hospital of University of South China, Hengyang, Hunan, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Liu
authors.affiliation: Department of Thoracic Surgery 2, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, China. jiangguanmin@hnszlyy.com whongsh@mail.sysu.edu.cn liangjianping@hnszlyy.com.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Liang
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000069286:Bortezomib / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D050794:STAT1 Transcription Factor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D000069286:Bortezomib; D007371:Interferon-gamma