Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid

项目摘要 逃避免疫反应是癌症的标志。“肿瘤免疫周期”始于对 肿瘤相关蛋白通过树突状细胞（DC），其在引流淋巴结中启动T细胞应答， 随后将这些抗肿瘤T细胞运输到肿瘤中以介导肿瘤溶解。肿瘤可以阻断 这个循环的一个或多个步骤来逃避免疫反应。靶向这种药物的治疗潜力 免疫逃避途径突出了免疫检查点抑制剂的临床成功， 癌症中的T细胞抑制。然而，在大多数实体瘤中不产生肿瘤反应性T细胞， 限制了免疫检查点抑制剂的效用。这种不能产生抗肿瘤T细胞的主要原因是 肿瘤微环境（TME）中DC的缺乏和功能障碍。虽然树突状细胞在肿瘤中很少见， 大量存在密切相关的细胞类型巨噬细胞。与DC相反，肿瘤相关巨噬细胞 （TAM）具有免疫抑制作用并促进肿瘤进展。DC和TAM都可以源自 但是我们对为什么单核细胞优先选择 在实体瘤中分化为免疫抑制性TAM而不是免疫刺激性DC。我们的长期 目的是了解TME中巨噬细胞和DC的发育和分化， 我们的首要目标是靶向这些细胞用于癌症免疫治疗。我以前开发了强大的 肉瘤（一种致死性实体瘤）的基因工程小鼠模型，以及 研究抗原呈递细胞。在我的实验室里使用这些工具，我最近发现， 视黄酸阻断DC但促进TAM从单核细胞分化。此外，我发现， 细胞因子IL 13促进肿瘤细胞中RA的产生。基于这些发现，我们的中心假设是， IL-13诱导的肿瘤细胞产生RA阻止TME产生免疫刺激性DC 单核细胞我认为这是实体瘤中免疫逃避的主要途径。我们的两个具体目标将 阐明RA影响单核细胞分化和抗原呈递的机制（Aim 1）， 揭示IL 13如何控制TME中RA的产生（目标2）。我们还将研究针对这一点的价值 肿瘤免疫治疗的途径。这项工作将对我们理解 实体瘤免疫调节，并建立一种新的方法，在实体瘤免疫治疗的基础上， 靶向APC中的RA信号传导。我们的工作是创新的，因为它将开辟研究的新途径 类维生素A信号在APC分化和肿瘤免疫中的作用。

Project Summary Evading immune responses is a hallmark of cancer. The `tumor-immunity cycle' begins with the processing of tumor-associated proteins by dendritic cells (DC), which initiate a T-cell response in draining lymph nodes, followed by the trafficking of these anti-tumor T cells into the tumor to mediate tumor lysis. Tumors can block one or more steps of this cycle to evade immune responses. The therapeutic potential of targeting such immune-evasion pathways is highlighted by the clinical success of immune checkpoint inhibitors that alleviates T cell suppression in cancer. However, tumor-reactive T cells are not generated in most solid tumors, which limit the utility of immune checkpoint inhibitors. A major reason for this failure to generate anti-tumor T cells is the paucity and dysfunction of DCs in the tumor microenvironment (TME). While DCs are rare inside tumors, a closely related cell type, macrophages, are abundant. In contrast to DCs, tumor-associated macrophages (TAMs) are immunosuppressive and promote tumor progression. Both DCs and TAMs can originate from monocytes but there is a major knowledge gap in our understanding of why monocytes preferentially differentiate into immunosuppressive TAMs but not immunostimulatory DCs in solid tumors. Our long-term interest is to understand the development and differentiation of macrophages and DCs in the TME with the overarching goal of targeting these cells for cancer immunotherapy. I previously developed powerful genetically engineered mouse models of sarcomas, a type of lethal solid tumor, as well as mouse models to study antigen-presenting cells. Using these tools in my laboratory, I recently discovered that tumor cell-derived retinoic acid blocks DC but promotes TAM differentiation from monocytes. Furthermore, I have found that the cytokine IL13 promotes RA production in tumor cells. Based on these findings, our central hypothesis is that IL13-induced RA production by tumor cells prevents the generation of immunostimulatory DCs from TME monocytes. I posit that this is a major pathway of immune evasion in solid tumors. Our two specific aims will delineate the mechanism by which RA affects monocyte differentiation and antigen presentation (Aim 1) and uncover how IL13 controls RA production in TME (Aim 2). We will also examine the value of targeting this pathway for tumor immunotherapy. This work will have significant impact on our understanding of immunomodulation in solid tumors and establish a new approach in solid tumor immunotherapy based on targeting RA signaling in APCs. Our work is innovative because it will open new avenues of research into the role of retinoid signaling in APC differentiation and tumor immunity.