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: 8886037
• 负责人: Tracy L McGaha
• 金额: $ 34.73万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886037
• 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; factor C; in vivo; insight; macrophage; melanoma; nanoparticle; new therapeutic target; prevent; public health relevance; response; sensor; theories; transcription factor; tumor

 DESCRIPTION (provided by applicant): 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 MFs) 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 MFs. Deletion of MZ MFs abrogated tumor-induced splenic IL-6 and CCL2 expression and MDSC expansion suggesting a previously unknown mechanistic relationship between MZ MFs 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/EBPß. In this proposal we hypothesize MZ MF-dependent expansion of MDSCs and GCN2-driven acquisition of suppressive function are related with MZ MFs providing the early signals driving MDSC recruitment to the MZ and activation. Our project will examine how tumors impact MZ MF 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.

 描述（由申请人提供）：脾边缘区（MZ）中肿瘤驱动的骨髓源性抑制细胞（MDSC）扩张对于抑制体内抗肿瘤 CD8+ T 细胞反应至关重要。边缘区驻留巨噬细胞（MZ MF）是循环中细胞碎片的关键传感器，可驱动早期耐受性反应并防止自身免疫。发现MZ中与MZ MF接触的MDSC显着扩增，删除MZ MF消除了肿瘤诱导的脾IL-6和CCL2表达以及MDSC扩增，这表明MZ MF和MDSC之间存在先前未知的机制关系。诱导分化和抑制需要整合应激反应的 GCN2 臂的参与，这反过来又驱动骨髓分化因子 C/EBPß 的表达。我们支持 MDSC 的 MZ MF 依赖性扩张和 GCN2 驱动的抑制功能的获得与 MZ MF 提供驱动 MDSC 募集到 MZ 和激活的早期信号有关。我们的项目将研究肿瘤如何影响 pro-MDSC 的 MZ MF 表达。如果成功，该项目的研究结果将为了解微环境和基质巨噬细胞在肿瘤介导的抑制过程中的贡献提供新的见解。并为癌症免疫治疗提供新的治疗靶点。