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一个标志。“肿瘤-免疫循环”始于对 树突状细胞(DC)的肿瘤相关蛋白，在引流淋巴结中启动T细胞反应， 然后将这些抗肿瘤T细胞运输到肿瘤中，介导肿瘤溶解。肿瘤可以阻断 这一循环中的一个或多个步骤，以逃避免疫反应。靶向此类药物的治疗潜力 免疫检查点抑制剂的临床成功突出了免疫逃避途径，它可以缓解 癌症中的T细胞抑制。然而，在大多数实体肿瘤中不产生肿瘤反应性T细胞，这是 限制免疫检查点抑制剂的使用。未能产生抗肿瘤T细胞的一个主要原因是 肿瘤微环境(TME)中树突状细胞的缺乏和功能障碍。虽然树突状细胞在肿瘤内很罕见，但 密切相关的细胞类型--巨噬细胞--非常丰富。与树突状细胞相比，肿瘤相关巨噬细胞 (TAMs)具有免疫抑制作用，并促进肿瘤进展。DC和TAM都可以起源于 单核细胞，但我们在理解为什么单核细胞优先 在实体瘤中分化为免疫抑制的TAM，而不是免疫刺激的DC。我们的长期合作 感兴趣的是了解TME中巨噬细胞和DC的发育和分化 以这些细胞为靶点进行癌症免疫治疗的首要目标。我之前开发了强大的 转基因小鼠肉瘤模型，一种致命的实体肿瘤，以及 研究抗原提呈细胞。在我的实验室里使用这些工具，我最近发现肿瘤细胞源于 维甲酸阻断DC，但促进向单核细胞分化。此外，我还发现 细胞因子IL13促进肿瘤细胞产生RA。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抑制TME免疫刺激DC的产生 单核细胞。我推测这是实体瘤免疫逃避的主要途径。我们的两个具体目标将 描述RA影响单核细胞分化和抗原提呈的机制(目标1)和 揭示IL13如何控制TME中RA的产生(目标2)。我们还将研究以此为目标的价值 肿瘤免疫治疗的途径。这项工作将对我们理解 实体瘤的免疫调节，建立一种新的实体瘤免疫治疗方法 针对APC中的RA信令。我们的工作具有创新性，因为它将为研究 维甲酸信号在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.