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

• 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
• 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

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.

项目摘要 逃避免疫反应是癌症的标志。 “肿瘤免疫周期”始于处理 树突状细胞（DC）与肿瘤相关的蛋白质，该蛋白在排水淋巴结中启动T细胞反应， 然后将这些抗肿瘤T细胞运输到肿瘤中以介导肿瘤裂解。肿瘤可以阻塞 该周期的一个或多个步骤逃避免疫反应。靶向这样的治疗潜力 免疫逃避途径是通过减轻免疫检查点抑制剂的临床成功来强调的 T细胞抑制癌症。但是，在大多数实体瘤中，肿瘤反应性T细胞均未产生 限制免疫检查点抑制剂的效用。这种未能产生抗肿瘤T细胞的主要原因是 DC在肿瘤微环境（TME）中的稀少和功能障碍。虽然DC在肿瘤中很少见 密切相关的细胞类型，巨噬细胞很丰富。与DC相反，与肿瘤相关的巨噬细胞 （TAM）是免疫抑制作用并促进肿瘤进展的。 DC和TAM都可以起源 单核细胞，但我们对为什么单核细胞优先了解的是一个主要的知识差距 分化为免疫抑制性TAM，而不是实体瘤中的免疫刺激DC。我们的长期 兴趣是了解与TME中巨噬细胞和DC的发展和分化 将这些细胞靶向癌症免疫疗法的总体目标。我以前开发了强大的 肉瘤的基因工程小鼠模型，一种致命的实体瘤，以及小鼠模型 研究抗原呈递细胞。我最近在实验室中使用这些工具，最近发现肿瘤细胞衍生 视黄酸会阻断直流，但促进了与单核细胞的TAM分化。此外，我发现 细胞因子IL13促进肿瘤细胞中的RA产生。基于这些发现，我们的中心假设是 IL13诱导的肿瘤细胞的RA产生可防止从TME产生免疫刺激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 描述RA影响单核细胞分化和抗原表现的机制（AIM 1）和 发现IL13如何控制TME中的RA产量（AIM 2）。我们还将研究目标的价值 肿瘤免疫疗法的途径。这项工作将对我们对 在实体瘤中进行免疫调节，并基于实体瘤免疫疗法建立新方法 靶向APC中的RA信号。我们的工作具有创新性，因为它将为研究的新途径开放 类视黄度信号在APC分化和肿瘤免疫中的作用。