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

项目摘要 肿瘤驱动的髓源性抑制细胞（MDSC）在边缘区扩增 (MZ)脾脏的免疫应答对于抑制体内抗肿瘤CD 8 + T细胞应答至关重要。 在以前发表的数据中，我们报道了边缘区居民巨噬细胞（MZ）， MΦs）是循环中细胞碎片驱动早期致耐受性的关键传感器 反应和预防自身免疫。当我们检查肿瘤的脾脏时- 我们发现在与MZ接触的MZ中MDSC显著扩增 MΦs。MZ MΦs缺失消除肿瘤诱导的脾IL-6和CCL 2表达 和MDSC扩张表明了一种以前未知的机制关系 MZ MΦ和MDSC之间的关系。此外，我们发现MDSC激活诱导 分化和抑制需要整合的GCN 2臂的接合。 应激反应，进而驱动髓样分化因子的表达 C/EBPβ。在该提议中，我们假设MDSC的MZ MΦ依赖性扩增， GCN 2驱动的抑制功能的获得与MZ MΦ有关， 早期信号驱动MDSC招募到MZ和激活。我们的项目将 检查肿瘤如何影响MZ MΦ表达pro-MDSC因子，并确定 这与MDSC前体中GCN 2信号激活之间的功能关系。如果 成功，从这个项目的结果将提供新的见解的贡献 微环境和基质巨噬细胞在肿瘤介导的抑制性 方法以及为癌症免疫治疗提供新的治疗靶点。

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.