Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer

项目摘要 免疫抑制性巨噬细胞与癌症相关的炎症和治疗相关的炎症有关。 癌症的耐药性，包括化疗和免疫治疗，因此代表了有吸引力的治疗方法， 目标的巨噬细胞可极化为极端的M1或M2表型，这取决于环境 线索尽管肿瘤微环境中的巨噬细胞表型更为复杂，但很明显， 免疫抑制性肿瘤相关巨噬细胞（TAM）在表型上更类似于M2样 巨噬细胞在前期的研究中，我们发现转录因子c-Maf在大肠杆菌中高表达， 小鼠和人极化M2巨噬细胞和免疫抑制性TAM。此外，天然产物 酵母衍生颗粒β-葡聚糖处理显著下调c-Maf表达， 增强小鼠的T细胞反应。我们还证明了M1和M2巨噬细胞具有不同的 代谢谱和c-Maf调节许多与糖酵解相关的基因。根据这些初步研究， 我们假设转录因子c-Maf是一个重要的控制器和代谢检查点， 用于免疫抑制TAM功能活性。提出了三个目标。目标1确定了 c-Maf在免疫抑制性TAM中调节的细胞和分子机制。我们将 研究肿瘤分泌因子是否调节TAM中c-Maf的表达。我们还将确定如何 Raf-1激酶途径调节c-Maf和c-Maf相关基因表达。最后，我们将测试 TAM中c-Maf功能的丧失显著延迟肿瘤进展和转移。目标2确定 采用系统代谢组学方法，研究c-Maf对TAM代谢途径的调控。我们将首先 使用稳定同位素解析代谢组学（SIRM）方法确定TAM代谢途径。 此外，我们将确定哪些代谢途径受c-Maf的调节。最后我们将确定 代谢重编程在β-葡聚糖介导的TAM功能转换中的致病作用。目标3 确定dectin-1激动剂β-葡聚糖是否调节人非小细胞肺的TAM功能 癌症（NSCLC）通过c-Maf途径。我们将确定β-葡聚糖治疗是否下调c- 人NSCLC TAM中Maf表达和改变c-Maf调节基因。我们还将确定 人TAM功能在β-葡聚糖处理后逆转。最后，我们将研究β-葡聚糖是否 NSCLC患者中的治疗下调c-Maf表达并改变单核细胞抑制 功能这项提案的总体目标是了解转录调控， 通过c-Maf的免疫抑制性TAM，建立了转录因子c-Maf作为人类免疫调节的新靶点。 癌症免疫疗法

Project Summary Immunosuppressive macrophages have been linked to cancer-related inflammation and therapeutic resistance in cancer including chemotherapy and immunotherapy, thus representing attractive therapeutic targets. Macrophages can be polarized into extreme M1 or M2 phenotype depending on the environmental cues. Although macrophage phenotype within the tumor microenvironment is more complicated, it is clear that immunosuppressive tumor-associated macrophages (TAM) phenotypically more resemble M2-like macrophages. In the preliminary studies, we discovered that transcription factor c-Maf is highly expressed in mouse and human polarized M2 macrophages and immunosuppressive TAM. In addition, natural product yeast-derived particulate β-glucan treatment significantly downregulates c-Maf expression leading to enhanced T cell responses in mice. We also demonstrated that M1 and M2 macrophages have distinct metabolic profiles and c-Maf regulates many genes related to glycolysis. Based on these preliminary studies, we hypothesize that transcription factor c-Maf is an essential controller and a metabolic checkpoint for immunosuppressive TAM functional activity. Three Aims are proposed. Aim 1 determines the cellular and molecular mechanisms by which c-Maf is regulated in immunosuppressive TAM. We will investigate whether tumor secreted factors regulate c-Maf expression in TAM. We will also determine how the Raf-1 kinase pathway regulates c-Maf and c-Maf-related gene expression. Finally, we will test whether loss of function of c-Maf in TAM significantly delays tumor progression and metastasis. Aim 2 determines which TAM metabolic pathway(s) is regulated by c-Maf using systems metabolomics approach. We will first determine TAM metabolic pathways using Stable Isotope Resolved Metabolomics (SIRM) approach. Furthermore, we will determine which metabolic pathways are regulated by c-Maf. Finally we will determine the causative role of metabolic reprogramming in β-glucan-mediated TAM functional conversion. Aim 3 determines whether the dectin-1 agonist β-glucan modulates TAM function of human non-small cell lung cancer (NSCLC) via the c-Maf pathway. We will determine whether β-glucan treatment downregulates c- Maf expression and alters c-Maf-regulated genes in human NSCLC TAM. We will also determine whether human TAM functions are reversed upon β-glucan treatment. Finally, we will examine whether β-glucan treatment in patients with NSCLC downregulates c-Maf expression and alters monocyte suppressive function. The overall goal of this proposal is to understand the transcriptional regulation of immunosuppressive TAM by c-Maf and establish the transcription factor c-Maf as a novel target for human cancer immunotherapy.