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

项目摘要 肿瘤驱动的髓系来源的抑制细胞(MDSC)在边缘区的扩张 脾(MZ)在体内抑制抗肿瘤CD8+T细胞反应中起关键作用。 在之前发表的数据中，我们报道了边缘带驻留巨噬细胞(MZ) MΦS)是循环中细胞碎片驱动早期耐受的关键传感器 反应和防止自身免疫。当我们检查肿瘤的脾时- 在与MZ接触的小鼠中，我们发现MZ中的MDSCs显著扩张 MΦS。缺失MZ MΦS可抑制肿瘤诱导的脾IL-6和CCL2的表达 和MDSC膨胀表明了一种以前未知的机械关系 在MZ MΦS和MDSC之间。此外，我们还发现MDSC被诱导激活 区分和抑制需要集成的GCN2臂接合 应激反应，进而推动髓系分化因子的表达 C/eBPβ.在这个建议中，我们假设MDSC的MZ MΦ依赖的扩展和 GCN2驱动的抑制功能习得与MZ MΦS提供的 早期信号驱动MDSC招募到MZ并激活。我们的项目将 检测肿瘤对MZ-MΦ表达的影响，并确定 这与MDSC前体中GCN2信号激活之间的功能关系。如果 如果成功，这个项目的发现将为我们提供对该贡献的新见解 微环境和间质巨噬细胞在肿瘤介导的抑制中的作用 并为癌症免疫治疗提供了新的治疗靶点。

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.