The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development

边缘区巨噬细胞和免疫代谢在肿瘤驱动的 MDSC 发育中的作用

• 批准号: 9183751
• 负责人: Tracy L McGaha
• 金额: $ 24.71万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9183751
• 关键词: Amino Acids; Animal Model; Antigens; Arginine; Automobile Driving; Blood Circulation; CCAAT-Enhancer-Binding Proteins; CCL2 gene; CD8B1 gene; Cell Differentiation process; Cells; Characteristics; Chemotaxis; Consumption; Cytotoxic T-Lymphocytes; Data; Data Reporting; Dendritic Cells; Development; Figs - dietary; Immune; Immune response; Immunity; Immunosuppression; Inflammation; Inflammatory; Interleukin-6; Lymphocyte Activation; Lymphoma; Macrophage Activation; Malignant Neoplasms; Mediating; Metabolism; Molecular; Molecular Profiling; Mus; Myelogenous; Pathway interactions; Phenotype; Phosphotransferases; Play; Population; Process; Proteins; Publishing; Reporting; Research; Role; Signal Transduction; Small Interfering RNA; Spleen; Starvation; Stress; Suppressor-Effector T-Lymphocytes; T cell response; Testing; Therapeutic; Time; Tumor Antigens; Vaccine Antigen; Work; arginase; arm; autocrine; base; biological adaptation to stress; cancer cell; chemotherapy; cytokine; exosome; factor C; in vivo; insight; macrophage; melanoma; nanoparticle; new therapeutic target; prevent; response; sensor; theories; transcription factor; tumor

Project Summary Tumor-driven myeloid-derived suppressor cell (MDSC) expansion in the marginal zone (MZ) of the spleen is critical for suppression of anti-tumor CD8+ T cell responses in vivo. In previously published data we reported that marginal zone-resident macrophages (MZ MΦs) are critical sensors for cellular debris in circulation driving early tolerogenic responses and preventing auto-immunity. When we examined the spleens of tumor- bearing mice we found significant expansion of MDSCs in the MZ in contact with MZ MΦs. Deletion of MZ MΦs abrogated tumor-induced splenic IL-6 and CCL2 expression and MDSC expansion suggesting a previously unknown mechanistic relationship between MZ MΦs and MDSCs. Moreover, we found MDSC activation induced differentiation and suppression required engagement of the GCN2 arm of the integrated stress response which, in turn, drove expression of the myeloid differentiation factor C/EBPβ. In this proposal we hypothesize MZ MΦ-dependent expansion of MDSCs and GCN2-driven acquisition of suppressive function are related with MZ MΦs providing the early signals driving MDSC recruitment to the MZ and activation. Our project will examine how tumors impact MZ MΦ expression of pro-MDSC factors and determine the functional relationship between this and GCN2 signal activation in MDSC precursors. If successful, the findings from this project would provide new insight into the contribution of microenvironment and stromal macrophages in tumor-mediated suppressive processes as well as provide novel therapeutic targets for cancer immuno-therapy.

项目概要 边缘区肿瘤驱动的骨髓源性抑制细胞 (MDSC) 扩张 脾脏 (MZ) 对于抑制体内抗肿瘤 CD8+ T 细胞反应至关重要。 在之前发表的数据中，我们报道了边缘区驻留巨噬细胞（MZ MΦs）是循环中细胞碎片的关键传感器，驱动早期耐受性 反应和预防自身免疫。当我们检查肿瘤的脾脏时 我们发现与妊娠小鼠接触的妊娠区 MDSC 显着扩增 MΦs。 MZ MΦs 的缺失消除了肿瘤诱导的脾脏 IL-6 和 CCL2 表达 和 MDSC 扩展表明以前未知的机制关系 MZ MΦ 和 MDSC 之间。此外，我们发现 MDSC 激活诱导 分化和抑制需要集成的 GCN2 臂的参与 应激反应反过来又驱动骨髓分化因子的表达 C/EBPβ。在本提案中，我们假设 MDSC 的 MZ MΦ 依赖性扩展，并且 GCN2 驱动的抑制功能获取与 MZ MΦ 相关，提供 早期信号驱动 MDSC 募集至 MZ 并激活。我们的项目将 检查肿瘤如何影响 MDSC 因子的 MZ MΦ 表达并确定 这与 MDSC 前体中 GCN2 信号激活之间的功能关系。如果 成功后，该项目的研究结果将为我们的贡献提供新的见解 微环境和基质巨噬细胞在肿瘤介导的抑制中的作用 过程并为癌症免疫治疗提供新的治疗靶点。