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

• 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
• 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' -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

 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（由申请人提供）：虽然黑色素瘤免疫疗法开始在临床上显示出有益的结果，但目前只有一小部分患者从这种治疗形式中受益。这些癌症免疫治疗方法的开发主要集中在增强 T 细胞的功能，而较少的工作致力于开发增强抗原呈递细胞活性的策略。树突状细胞 (DC) 是有效的抗原呈递细胞，能够激活肿瘤抗原特异性 T 细胞并指导其功能。据信，目前免疫治疗药物的功效有限，很大程度上是因为 由于发展癌症所使用的方法的演变，以避免被宿主免疫系统检测和破坏。最近的研究表明，癌症能够主动耐受局部 DC，使其能够促进调节性 T 细胞 (Treg) 的扩增并维持免疫耐受状态。肿瘤免疫逃避的一个重要组成部分已被确定为吲哚胺 2,3-双加氧酶 (IDO) 免疫调节酶，它将色氨酸氨基酸转化为犬尿氨酸。该过程抑制传统 T 细胞活性并驱动 Tregs 的发育。黑色素瘤和其他实体瘤促进这种 DC 耐受过程的分子机制仍然未知。 先前的研究表明，黑色素瘤表达高水平的几种 Wnt 配体，并且 Wnt5a 表达与不良预后相关。我们已经确定 Wnt5a 是黑色素瘤微环境中驱动 DC 依赖性 Tregs 分化和扩张的主导因素。尽管这个过程部分依赖于 Wnt5a 介导的 DC IDO 表达上调，但我们的初步数据现在表明，这种 DC 耐受程序由 DC 代谢的额外改变组成。我们现在提出一种策略来扩展这些研究，方法是：1) 表征这种新型 Wnt5a-ß-catenin 依赖性途径对抗黑色素瘤免疫和黑色素瘤进展的影响，2) 确定 Wnt5a-ß-catenin 信号传导途径是否有助于免疫治疗耐药性以及该过程是否可以通过药理学逆转，以及 3) 阐明 Wnt5a 诱导的代谢改变 DC 以及这些代谢变化如何有助于产生免疫耐受的微环境。为了实现这些目标，我们计划利用一种基因工程小鼠模型，该模型在生理上类似于人类黑色素瘤，并且可以更深入地分析正在发展的恶性肿瘤与局部免疫反应之间的相互作用。该项目旨在定义一种新的免疫逃避途径，并在此过程中提供一种策略，既可以增强现有免疫治疗方法的疗效，又可以扩大可能受益于肿瘤免疫治疗的患者群体。