Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in Cancer

项目摘要 免疫抑制巨噬细胞与癌症相关的炎症和治疗有关 癌症中的耐药性，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。巨噬细胞可以被极化成极端的M1或M2表型，这取决于环境 暗示。尽管肿瘤微环境中的巨噬细胞表型更为复杂，但很明显 免疫抑制肿瘤相关巨噬细胞()的表型更像M2样细胞 巨噬细胞。在初步研究中，我们发现转录因子c-maf在 小鼠和人M2巨噬细胞极化与免疫抑制。此外，天然产物 酵母衍生颗粒β-葡聚糖显著下调c-maf表达，导致 增强小鼠的T细胞反应。我们还证明了M1和M2巨噬细胞具有明显的 代谢谱和c-Maf调节许多与糖酵解有关的基因。根据这些初步研究， 我们假设转录因子c-maf是一个重要的控制者和代谢检查点。 为免疫抑制的功能活性。提出了三个目标。目标1决定了 C-maf在免疫抑制中的细胞和分子调控机制。我们会 探讨肿瘤分泌因子对c-maf表达的调节作用。我们还将确定如何 Raf-1激酶通路调节c-Maf及其相关基因的表达。最后，我们将测试 患者c-maf功能缺失显著延缓肿瘤的进展和转移。目标2决定 利用系统代谢组学的方法，发现代谢途径(S)受c-MAF调控。我们将首先 用稳定同位素分辨代谢组学方法确定的代谢途径。 此外，我们将确定c-Maf调控哪些代谢途径。最终我们将确定 代谢重编程在β-葡聚糖介导的功能转换中的作用目标3 确定Dectin-1激动剂β-葡聚糖是否调节人非小细胞肺的功能 非小细胞肺癌(NSCLC)通过c-Maf途径发生。我们将确定β-葡聚糖治疗是否下调c- MAF在人非小细胞肺癌细胞中的表达及其对c-MAF调控基因的影响我们还将确定是否 经β-葡聚糖处理后，人的功能发生逆转。最后，我们将检查β-葡聚糖是否 非小细胞肺癌患者的治疗下调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理解转录调控 C-maf对的免疫抑制作用及人新靶点转录因子c-maf的建立 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.