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

视黄酸对肿瘤微环境中抗原呈递细胞的调节

基本信息

批准号：
10051410
负责人：
Malay Haldar
金额：
$ 36.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-03 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10051410
关键词：
Affect Antigen Presentation Antigen-Presenting Cells Antigens Biology Cell Death Cell Differentiation process Cell Separation Cells Cellular biology Clinical Cytolysis Data Dendritic Cells Dendritic cell tumor Detection Development Differentiation Antigens Enzymes Failure Flow Cytometry Functional disorder Generations Genetic Genetically Engineered Mouse Goals Hematopoietic IRF4 gene Immune Evasion Immune checkpoint inhibitor Immune response Immune system Immunosuppression Immunotherapy Interleukin-13 Interleukin-2 Knowledge Laboratories Malignant Neoplasms Mediating Modeling Molecular Neoplasm Metastasis Ovalbumin Pathway interactions Patient Care Pharmacology Positioning Attribute Pre-Clinical Model Production Proteins Public Health Radiation Radiation therapy Regulation Reporting Research Resources Retinoids Role Signal Transduction Solid Neoplasm Source T cell response T-Lymphocyte Testing Therapeutic Tissues Tretinoin Tumor Antigens Tumor Immunity Tumor-Derived Tumor-associated macrophages Work adaptive immune response angiogenesis anti-tumor immune response base cancer cell cancer immunotherapy cell type cytokine draining lymph node immunoregulation immunosuppressive macrophages in vivo inhibitor/antagonist innovation interest macrophage monocyte mouse model neoplasm immunotherapy neoplastic cell novel novel strategies prevent sarcoma success tool trafficking transcription factor tumor tumor growth tumor microenvironment tumor progression

项目摘要

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.

项目概要逃避免疫反应是癌症的一个标志。 “肿瘤-免疫循环”始于处理树突状细胞 (DC) 产生的肿瘤相关蛋白，在引流淋巴结中启动 T 细胞反应，随后将这些抗肿瘤 T 细胞运输到肿瘤中以介导肿瘤溶解。肿瘤可以阻断该循环的一个或多个步骤来逃避免疫反应。靶向此类药物的治疗潜力免疫检查点抑制剂的临床成功凸显了免疫逃避途径，该抑制剂减轻了癌症中的 T 细胞抑制。然而，大多数实体瘤中不会产生肿瘤反应性 T 细胞，这限制免疫检查点抑制剂的效用。无法产生抗肿瘤 T 细胞的一个主要原因是肿瘤微环境（TME）中 DC 的缺乏和功能障碍。虽然 DC 在肿瘤内很少见，密切相关的细胞类型巨噬细胞数量丰富。与 DC 相比，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 都可以源自单核细胞，但我们对为什么单核细胞优先的理解存在重大知识差距在实体瘤中分化为免疫抑制性 TAM，但不分化为免疫刺激性 DC。我们的长期兴趣是了解 TME 中巨噬细胞和 DC 的发育和分化靶向这些细胞进行癌症免疫治疗的总体目标。我以前开发过强大的肉瘤（一种致命的实体瘤）的基因工程小鼠模型，以及肉瘤的小鼠模型研究抗原呈递细胞。在我的实验室中使用这些工具，我最近发现肿瘤细胞衍生的视黄酸阻断 DC，但促进 TAM 从单核细胞分化。此外，我发现细胞因子 IL13 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 IL13诱导肿瘤细胞产生RA可阻止TME产生免疫刺激性DC 单核细胞。我认为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呈递的机制（目标 1）和揭示 IL13 如何控制 TME 中 RA 的产生（目标 2）。我们还将研究针对此目标的价值肿瘤免疫治疗途径。这项工作将对我们的理解产生重大影响实体瘤的免疫调节，并在此基础上建立实体瘤免疫治疗的新方法靶向 APC 中的 RA 信号传导。我们的工作是创新的，因为它将开辟新的研究途径类维生素A信号在APC分化和肿瘤免疫中的作用。