B7-H4 EXPRESSION ID'S A SUPPRESSIVE MACROPHAGE POPULATION IN OVARIAN CARCINOMA

B7-H4 表达是卵巢癌中的抑制性巨噬细胞群

• 批准号: 7562386
• 负责人: I KRYCZEK
• 金额: $ 3.04万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562386
• 关键词: Computer Retrieval of Information on Scientific Projects Database; Disease regression; Ectopic Expression; Family; Funding; Grant; Granulocyte-Macrophage Colony-Stimulating Factor; Immune response; Immunity; Institution; Interleukin-10; Interleukin-4; Interleukin-6; Malignant Neoplasms; Malignant neoplasm of ovary; Ovarian Carcinoma; Population; Research; Research Personnel; Resources; Source; Suppressor-Effector T-Lymphocytes; Surface; T-Lymphocyte; Tumor Antigens; Tumor Immunity; United States National Institutes of Health; arginase; cytokine; human NOS2A protein; in vivo; macrophage; neoplastic cell; novel; novel strategies; ovarian neoplasm; tumor; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Tumor-associated macrophages are a prominent component of ovarian cancer stroma and contribute to tumor progression. B7-H4 is a recently identified B7 family molecule. We show that primary ovarian tumor cells express intracellular B7-H4, whereas a fraction of tumor macrophages expresses surface B7-H4. B7-H4+ tumor macrophages, but not primary ovarian tumor cells, suppress tumor-associated antigen-specific T cell immunity. Blocking B7-H4-, but not arginase-, inducible nitric oxide synthase or B7-H1 restored the T cell stimulating capacity of the macrophages and contributes to tumor regression in vivo. Interleukin (IL)-6 and IL-10 are found in high concentrations in the tumor microenvironment. These cytokines stimulate macrophage B7-H4 expression. In contrast, granulocyte/macrophage colony-stimulating factor and IL-4, which are limited in the tumor microenvironment, inhibit B7-H4 expression. Ectopic expression of B7-H4 makes normal macrophages suppressive. Thus, B7-H4+ tumor macrophages constitute a novel suppressor cell population in ovarian cancer. B7-H4 expression represents a critical checkpoint in determining host responses to dysfunctional cytokines in ovarian cancer. Blocking B7-H4 or depleting B7-H4+ tumor macrophages may represent novel strategies to enhance T cell tumor immunity in cancer.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肿瘤相关巨噬细胞是卵巢癌间质的重要组成部分，并有助于肿瘤进展。B7-H4是最近发现的B7家族分子。我们发现，原发性卵巢肿瘤细胞表达细胞内B7-H4，而一部分肿瘤巨噬细胞表达表面B7-H4。B7-H4+肿瘤巨噬细胞而非原发性卵巢肿瘤细胞抑制肿瘤相关抗原特异性T细胞免疫。阻断B7-H4-，而不是B7-H1-，诱导型一氧化氮合酶或B7-H1恢复巨噬细胞的T细胞刺激能力，并有助于体内肿瘤消退。在肿瘤微环境中发现高浓度的白细胞介素（IL）-6和IL-10。这些细胞因子刺激巨噬细胞B7-H4表达。相反，粒细胞/巨噬细胞集落刺激因子和IL-4，这是有限的肿瘤微环境，抑制B7-H4的表达。B7-H4的异位表达使正常巨噬细胞受到抑制。因此，B7-H4+肿瘤巨噬细胞构成了卵巢癌中一种新的抑制细胞群。B7-H4表达是决定卵巢癌中宿主对功能失调细胞因子反应的关键检查点。阻断B7-H4或消耗B7-H4+肿瘤巨噬细胞可能代表增强癌症中T细胞肿瘤免疫的新策略。