Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion

黑色素瘤介导的树突状细胞耐受和免疫逃避

基本信息

批准号：
9310397
负责人：
Brent Allen Hanks
金额：
$ 16.51万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-04 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310397
关键词：
5&apos -AMP-activated protein kinase Address Amino Acids Antigen Presentation Antigen-Presenting Cells Automobile Driving CD8-Positive T-Lymphocytes Cellular Metabolic Process Chemicals Clinic Clinical Clinical Trials Data Dendritic Cells Dendritic cell activation Detection Development Effectiveness Enzymes Evolution Gene Targeting Generations Genetically Engineered Mouse Glycolysis Human Immune Evasion Immune Tolerance Immune checkpoint inhibitor Immune response Immune system Immunity Immunologic Monitoring Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Kynurenine Ligands Malignant Neoplasms Mediating Metabolic Metabolic Pathway Metabolism Metastatic Melanoma Methods Modeling Molecular Pathway interactions Patients Pharmacology Phenotype Play Population Process Progression-Free Survivals Protein Kinase Regulatory T-Lymphocyte Resistance Role Sentinel Lymph Node Signal Pathway Signal Transduction Solid Neoplasm T-Cell Development T-Lymphocyte Testing Therapeutic Time Tryptophan Tryptophan 2,3 Dioxygenase Tumor Antigens Tumor Burden Tumor Immunity Tumor-Derived Up-Regulation Work beta catenin cancer immunotherapy immunoregulation in vivo inhibitor/antagonist insight melanoma neoplasm immunotherapy new therapeutic target novel oncology outcome forecast patient population patient subsets physiologic model programs public health relevance response sensor targeted agent tumor tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): While melanoma immunotherapy is starting to show beneficial results in the clinic, only a subset of patients currently benefit from this form of treatment. The development of these cancer immunotherapy approaches has primarily focused on enhancing the function of the T cell while much less work has been devoted to developing strategies to enhance antigen-presenting cell activity. Dendritic cells (DCs) are potent antigen- presenting cells that are capable of both activating tumor antigen-specific T cells and directing their function. It is believed that the limited efficacy of current immunotherapy agents is largely due to the evolution of methods utilized by developing cancers to avoid detection and destruction by the host immune system. Recent work has shown that cancers are capable of actively tolerizing local DCs, enabling them to promote the expansion of regulatory T cells (Tregs) and maintain a state of immune tolerance. One important component of tumor immune evasion has been determined to be the indoleamine 2,3-dioxygenase (IDO) immunoregulatory enzyme that converts the tryptophan amino acid into kynurenine. This process suppresses conventional T cell activity and drives the development of Tregs. The molecular mechanisms utilized by melanomas and other solid tumors to promote this DC tolerization process remain unknown. Previous work has shown that melanomas express high levels of several Wnt ligands and that Wnt5a expression has been associated with a poor prognosis. We have determined that Wnt5a is the dominant factor driving DC-dependent differentiation and expansion of Tregs within the melanoma microenvironment. Although this process is partially dependent on Wnt5a-mediated upregulation of DC IDO expression, our preliminary data now suggests that this DC tolerization program is comprised of additional alterations in DC metabolism. We are now proposing a strategy to extend these studies by 1) characterizing the effect that this novel Wnt5a-ß-catenin-dependent pathway has on anti-melanoma immunity and melanoma progression, 2) determining if the Wnt5a-ß-catenin signaling pathway contributes to immunotherapy resistance and whether this process can be pharmacologically reversed, and 3) elucidating the metabolic alterations induced by Wnt5a in DCs and how these metabolic changes contribute to generating an immunotolerant microenvironment. To achieve these aims, we plan to utilize a genetically engineered mouse model that physiologically resembles human melanoma and allows for a more in-depth analysis of the interplay between a developing malignancy and the local immune response. This project seeks to define a novel immune evasion pathway and, in doing so, offers a strategy to both enhance the efficacy of currently available immunotherapy approaches and broaden the patient population that may benefit from tumor immunotherapy.

描述（由适用提供）：虽然黑色素瘤免疫疗法开始在诊所显示出益处，但目前只有一部分患者受益于这种治疗形式。这些癌症免疫疗法方法的开发主要集中在增强T细胞的功能上，而较少的工作已致力于制定策略来增强抗原呈现抗原的细胞活性。树突状细胞（DC）是潜在的抗原呈递细胞，能够激活肿瘤抗原特异性T细胞并指导其功能。据认为，当前免疫疗法剂的有限效率在很大程度上是由于通过开发癌症来避免被宿主免疫系统检测和破坏的方法所使用的方法的演变。最近的工作表明，癌症能够积极耐受局部DC，使它们能够促进调节性T细胞（TREG）的扩展并保持免疫耐受性。肿瘤免疫进化的一个重要组成部分已被确定为吲哚胺2,3-二加氧酶（IDO）免疫调节酶，将色氨酸氨基酸转化为kynurenine。该过程抑制了常规的T细胞活性并驱动Treg的发展。黑色素瘤和其他实体肿瘤利用的分子机制促进这种DC耐受过程仍然未知。先前的工作表明，黑色素瘤表达了高水平的几种Wnt配体，并且Wnt5a表达与预后不良有关。我们已经确定WNT5A是驱动DC依赖性的主要因素，尽管该过程部分取决于Wnt5a介导的DC IDO表达的上调，但我们的初步数据表明，该DC耐受性程序由DC代谢中的其他变化组成。现在，我们正在提出一种策略来扩展这些研究的策略，以1）表征这种新型的Wnt5A-ß-catenin依赖性途径对抗黑色素瘤的免疫和黑色素瘤的进展，2）确定WNT5A-A-ß-catenin信号通路是否有助于免疫疗法的抗性以及是否可以反复及3），并且在3中是否有任何依赖的方法。 DC以及这些代谢变化如何有助于产生免疫耐药的微环境。为了实现这些目标，我们计划利用一种具有物理类似于人类黑色素瘤的一般工程小鼠模型，并可以对发展中的恶性肿瘤与局部免疫疗法反应之间的相互作用进行更深入的分析。该项目旨在定义一种新型的免疫疗法途径，并为此提供了一种策略，既可以提高当前可用的免疫疗法方法的效率，又扩大了可能从肿瘤免疫疗法中受益的患者人群。