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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.