IDO-expressing plasmacytoid dendritic cells and tumors

表达 IDO 的浆细胞样树突状细胞和肿瘤

• 批准号: 7338670
• 负责人: David H. Munn
• 金额: $ 24.1万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-14 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338670
• 关键词: Address; Adoptive Transfer; Antigen Presentation; Antigen-Presenting Cells; Antigens; CD4 Positive T Lymphocytes; CD6 antigen; CD8B1 gene; Cell Cycle Arrest; Cell Cycle Progression; Cell Differentiation process; Cells; Class; Clinical; Condition; Dendritic Cells; Dioxygenases; Effector Cell; Employee Strikes; Enzymes; Immunologics; Immunosuppressive Agents; In Vitro; MHC Class I Genes; Modeling; Mus; Normal Cell; PTPRC gene; Pathologic; Peripheral; Phenotype; Population; Recruitment Activity; Role; Signal Transduction; Stress; T-Lymphocyte; Testing; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Antigens; Tumor Biology; Tumor-Derived; Withdrawal; anergy; cancer immunotherapy; in vitro Model; in vivo; indoleamine; insight; lymph nodes; response; tumor

DESCRIPTION (provided by applicant): Established tumors create a condition of immunologic unresponsiveness (tolerance) toward their own antigens. This constitutes a barrier to the clinical immunotherapy of cancer, and represents a striking model of acquired peripheral tolerance. This project will address the hypothesis that murine plasmacytoid dendritic cells (pDCs) expressing the tolerogenic enzyme indoleamine 2,3-dioxygenase (IDO) are selectively recruited to tumor-draining lymph nodes, where they create tolerance to tumor antigens. Aim 1 will test the hypothesis that IDO-expressing DCs from tumor-draining lymph nodes directly suppress T cell responses to tumor-derived antigens. This will first be done by adoptively transferring DCs isolated from murine tumor-draining lymph nodes, to test the hypothesis that these DCs render defined antigen-specific CD8+ T cells anergic in vivo, via IDO-induced tryptophan-withdrawal stress and cell-cycle arrest. Then a B16-OVA tumor model will be used with defined OVA-specific T cells to test the hypothesis that IDO expression in by pDCs in tumor-draining lymph nodes creates anergy to tumor-derived antigens in vivo. Aim 2 will test the hypothesis that IDO-expressing DCs from tumor-draining LNs amplify and sustain their effect by creating tumor-specific regulatory T cells. First, an in vitro model will be used to test the hypothesis that pDCs from tumor-draining lymph nodes suppress normal cell-cycle progression and effector-cell differentiation of CD4+ T cells via expression of IDO, and that this drives the conversion of naive CD4+ T cells into antigen-specific Tregs. Then an in vivo tumor model and defined CD4+ T cells will be used to test the hypothesis that antigen-presentation by IDO+ cells in vivo creates new antigen-specific Tregs against a nominal tumor-derived antigen. Finally, genetically defined mice will be used to test the hypothesis that pDCs in tumor-draining lymph nodes constitutively express IDO because they receive CTLA4->B7 signals delivered by tumor-specific Tregs. Taken together, the proposed studies will provide mechanistic insight into the role of IDO in the pathologic state of tolerance displayed toward tumors. This is relevant to the basic biology of tumors and to acquired peripheral tolerance, and has direct implications for clinical immunotherapy of cancer.

描述（由申请人提供）：已建立的肿瘤对其自身抗原造成免疫无反应（耐受）的情况。这构成了癌症临床免疫治疗的障碍，并代表了获得性外周耐受的惊人模型。该项目将解决这样的假设：表达耐受酶吲哚胺 2,3-双加氧酶 (IDO) 的小鼠浆细胞样树突状细胞 (pDC) 被选择性地募集到肿瘤引流淋巴结，在那里它们产生对肿瘤抗原的耐受性。目标 1 将检验以下假设：来自肿瘤引流淋巴结的表达 IDO 的 DC 直接抑制 T 细胞对肿瘤衍生抗原的反应。这将首先通过过继转移从小鼠肿瘤引流淋巴结分离的 DC 来完成，以测试这些 DC 通过 IDO 诱导的色氨酸撤退应激和细胞周期停滞使体内确定的抗原特异性 CD8 + T 细胞无反应性的假设。然后，B16-OVA 肿瘤模型将与确定的 OVA 特异性 T 细胞一起使用，以测试肿瘤引流淋巴结中 pDC 的 IDO 表达在体内产生对肿瘤衍生抗原的无反应性的假设。目标 2 将检验以下假设：来自肿瘤引流 LN 的表达 IDO 的 DC 通过产生肿瘤特异性调节 T 细胞来放大并维持其效应。首先，将使用体外模型来检验以下假设：来自肿瘤引流淋巴结的 pDC 通过 IDO 的表达抑制 CD4+ T 细胞的正常细胞周期进程和效应细胞分化，并且这驱动了初始 CD4+ 的转化T 细胞转化为抗原特异性 Tregs。然后，体内肿瘤模型和确定的 CD4+ T 细胞将用于测试以下假设：IDO+ 细胞在体内的抗原呈递会针对名义上的肿瘤衍生抗原产生新的抗原特异性 Tregs。最后，基因定义的小鼠将用于测试以下假设：肿瘤引流淋巴结中的 pDC 持续表达 IDO，因为它们接收肿瘤特异性 Tregs 传递的 CTLA4->B7 信号。总而言之，拟议的研究将为 IDO 在肿瘤耐受的病理状态中的作用提供机制见解。这与肿瘤的基础生物学和获得性外周耐受有关，并对癌症的临床免疫治疗具有直接影响。