Tumor plasmacytoid dendritic cells and tumor immunity

肿瘤浆细胞样树突状细胞与肿瘤免疫

• 批准号: 7282136
• 负责人: WEIPING ZOU
• 金额: $ 12.77万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7282136
• 关键词: T lymphocyte; cell cell interaction; cell growth regulation; cell proliferation; cellular immunity; clinical research; dendritic cells; female; flow cytometry; helper T lymphocyte; human subject; immunosuppression; interleukin 10; leukocyte activation /transformation; lymph nodes; malignant ascites; neoplasm /cancer immunology; ovary neoplasms; patient oriented research; suppressor T lymphocyte; surface antigens; tumor antigens; women' s health

DESCRIPTION (provided by applicant): Although most cancers possess tumor-associated antigens (TAA) that can serve as targets of the immune system, immunity is not effectively induced in most tumor-bearing hosts. Dysregulation of dendritic cell (DC) differentiation, function and trafficking may contribute to tumor immunopathogenesis. Malignant ascites contains viable tumor and immune cells, which we used as a model for the tumor environment. We identified a significant population of PDC, not MDC, in malignant ascites of patients with ovarian carcinoma. Our work demonstrate that tumor PDC induce TAA-specific IL-10+CCR7+CD8+ T cells. These T cells migrate with lymphoid homing molecule CCR7, and suppress MDC mediated TAA-specific protective tumor immunity. Further, MDC cannot recover the suppressive effects. More importantly, we show that tumor-mediated upregulation of PDC B7-H1 contributes to detrimental immunity induced by tumor PDC. We now extend these observations, and further demonstrate in detail the nature of TAA-specific T cell immunity induced by tumor PDC, and the underlying mechanisms. There exists a significant amount of PDC in tumor ascites. Tumor ascites harbors predominantly memory T cells. By examining the interaction between tumor ascites TAA-expressing PDC and tumor memory T cells, Aim 1 is to test our hypothesis that tumor PDC induce TAA-specific suppressive memory CD8+ T cell immunity. Lymph nodes (LNs) are the central priming sites for DC to initiate T cell immunity. LNs harbor predominantly naive T cells. Draining tumor LN-PDC co-localized with naive T cells. By examining the interaction between TAA expressing LN-PDC and LN naive T cells, Aim 2 is to test our hypothesis that draining tumor LNPDC induce TAA-specific suppressive naive CD8+ T cell immunity. B7-H1 is a member of the B7 T cell costimulatory family that induces T cell IL-10 and mediates tolerance/anergy. Tumor PDC highly express B7-H1 whose regulation and functional significance is unknown. Aim 3 is to test our hypothesis that tumor PDC B7-HI contributes to induce TAA-specific suppressive CD8+ T cell immunity.

描述（由申请人提供）：尽管大多数癌症具有肿瘤相关抗原（TAA），可以作为免疫系统的靶标，但在大多数肿瘤宿主中不能有效地诱导免疫。树突状细胞（DC）分化、功能和运输的失调可能与肿瘤的免疫发病有关。恶性腹水含有活的肿瘤细胞和免疫细胞，我们将其作为肿瘤环境的模型。我们在卵巢癌患者的恶性腹水中发现了大量的PDC，而不是MDC。我们的研究表明，肿瘤PDC诱导taa特异性IL-10+CCR7+CD8+ T细胞。这些T细胞随淋巴归巢分子CCR7迁移，抑制MDC介导的taa特异性保护性肿瘤免疫。此外，MDC不能恢复抑制效果。更重要的是，我们发现肿瘤介导的PDC B7-H1上调有助于肿瘤PDC诱导的有害免疫。我们现在扩展这些观察结果，并进一步详细证明肿瘤PDC诱导的taa特异性T细胞免疫的性质及其潜在机制。