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: 8967743
• 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/8967743
• 关键词: 5' -AMP-activated protein kinase; Address; Amino Acids; Antigen Presentation; Antigen-Presenting Cells; Automobile Driving; CD8B1 gene; Chemicals; Clinic; Clinical; Clinical Trials; Data; Dendritic Cells; Dendritic cell activation; Detection; Development; Effectiveness; Enzymes; Evolution; Figs - dietary; Gene Targeting; Generations; Genetically Engineered Mouse; Glycolysis; Health; Human; Immune; Immune Tolerance; 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; Phenotype; Play; Population; Process; Progression-Free Survivals; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Sentinel Lymph Node; Signal Pathway; Signal Transduction; Solid Neoplasm; T-Cell Activation; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Tryptophan; Tryptophan 2,3 Dioxygenase; Tumor Antigens; Tumor Burden; Tumor Immunity; Tumor-Derived; Up-Regulation; Work; beta catenin; cancer immunotherapy; in vivo; inhibitor/antagonist; insight; melanoma; mouse model; neoplasm immunotherapy; new therapeutic target; novel; oncology; outcome forecast; patient population; programs; response; sensor; 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(申请人提供)：虽然黑色素瘤免疫治疗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受益于这种形式的治疗。这些癌症免疫治疗方法的发展主要集中在增强T细胞的功能上，而致力于开发增强抗原提呈细胞活性的策略的工作要少得多。树突状细胞(DC)是一种强大的抗原提呈细胞，既能激活肿瘤抗原特异的T细胞，又能指导其功能。据认为，目前免疫治疗药物的疗效有限在很大程度上是 这是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树突状细胞，使其能够促进调节性T细胞(Treg)的扩张，并保持免疫耐受状态。肿瘤免疫逃避的一个重要组成部分被确定为吲哚胺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。这一过程抑制了传统的T细胞活性，并推动了Tregs的发展。黑色素瘤和其他实体肿瘤促进DC耐受过程的分子机制尚不清楚。以前的工作表明，黑色素瘤表达高水平的几个Wnt配体，Wnt5a的表达与预后不良有关。我们已经确定Wnt5a是在黑色素瘤微环境中驱动DC依赖的Tregs分化和扩展的主导因素。虽然这一过程部分依赖于Wnt5a介导的DC IDO表达上调，但我们的初步数据表明，这种DC耐受计划包括DC代谢的额外变化。我们现在提出了一种扩展这些研究的策略，通过1)表征这一新的Wnt5a-ü-catenin依赖通路在抗黑色素瘤免疫和黑色素瘤进展中的作用，2)确定Wnt5a-？catenin信号通路是否有助于免疫治疗耐药，以及这一过程是否可以被药物逆转，以及3)阐明Wnt5a诱导的DC的代谢变化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，我们计划利用一种在生理上类似于人类黑色素瘤的基因工程小鼠模型，并允许更深入地分析正在发展的恶性肿瘤和局部免疫反应之间的相互作用。该项目试图定义一种新的免疫逃避途径，并在这样做的同时，提供了一种策略，既提高了现有免疫治疗方法的有效性，又扩大了可能从肿瘤免疫治疗中受益的患者群体。