Melanoma-mediated Dendritic Cell Tolerization and Immune Evasion

 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，而致力于开发增强抗原呈递细胞活性的策略的工作要少得多。树突状细胞（DC）是有效的抗原呈递细胞，其能够活化肿瘤抗原特异性T细胞并指导其功能。据信，目前的免疫治疗剂的有限功效在很大程度上是由免疫治疗剂的免疫抑制剂引起的。 这是由于发展癌症以避免被宿主免疫系统检测和破坏的方法的进化。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（Tcells）的扩增并维持免疫耐受状态。已经确定肿瘤免疫逃避的一个重要组分是将色氨酸氨基酸转化为犬尿氨酸的吲哚胺2，3-双加氧酶（IDO）免疫调节酶。这一过程抑制了传统的T细胞活性，并推动了T细胞的发展。黑色素瘤和其他实体瘤促进这种DC耐受化过程的分子机制仍然未知。 先前的工作已经表明，黑色素瘤表达高水平的几种Wnt配体，并且Wnt 5a表达与不良预后相关。我们已经确定，Wnt 5a是驱动黑色素瘤微环境内TcB的DC依赖性分化和扩增的主导因素。尽管该过程部分依赖于Wnt 5a介导的DC IDO表达的上调，但我们的初步数据现在表明，该DC耐受化程序由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，通过1）表征这种新的Wnt 5a-β-连环蛋白依赖性途径对抗黑素瘤免疫和黑素瘤进展的作用，2）确定Wnt 5a-β-连环蛋白信号传导途径是否有助于免疫疗法抗性以及该过程是否可以逆转，以及3）阐明由Wnt 5a在DC中诱导的代谢改变以及这些代谢改变如何有助于产生免疫耐受微环境。为了实现这些目标，我们计划利用一种遗传工程小鼠模型，该模型在生理上类似于人类黑色素瘤，并允许对发展中的恶性肿瘤和局部免疫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的免疫逃避途径，并在此过程中提供了一种策略，既可以提高目前可用的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人群。

 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.