Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes- Resubmission

黑色素瘤浸润淋巴细胞代谢应激途径的表观遗传调控-重新提交

基本信息

批准号：
9888200
负责人：
Brian Koss
金额：
$ 3.07万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2020-12-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9888200
关键词：
Activated Lymphocyte Adoptive Cell Transfers Apoptosis Apoptotic Autologous BCL2 gene Cell Death Cells Cellular immunotherapy ChIP-seq Clip Data Dependence EZH2 gene Enhancers Environment Enzyme Inhibition Enzymes Epigenetic Process Face Family Fellowship Genetic Transcription Glucose Glycolysis Goals Histones Homologous Gene Hypoxia Immune Immune checkpoint inhibitor Immunosuppression Immunotherapy Incidence Infiltration Lead Lymphocyte Lymphocyte Activation Maps Mentors Metabolic Metabolic stress Metastatic Melanoma Methyltransferase MicroRNAs Monoclonal Antibodies N-terminal Oxidative Phosphorylation Pathway interactions Patients Play Post-Translational Protein Processing Proteomics Regulation Repression Role Scientist Solid Neoplasm Stress T cell therapy Testing Therapeutic Training Transgenic Mice Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Withdrawal Work career checkpoint inhibition checkpoint therapy combat deprivation epigenetic regulation experimental study fighting histone methyltransferase immunoregulation innovation lymphoid neoplasm melanoma mutant next generation novel novel strategies overexpression p19ARF pre-doctoral success transcriptome sequencing tumor tumor immunology tumor microenvironment

项目摘要

Epigenetic regulation of metabolic stress pathways in melanoma infiltrating lymphocytes Unleashing antitumor lymphocytes through checkpoint inhibition and adoptive cell therapies are incredibly promising strategies to fight metastatic melanoma. T cell adoptive therapies have shown success in patients that have failed checkpoint inhibitor therapies. The tumor-infiltrating lymphocytes (TIL) in adoptive therapy face a host of stresses as they encounter the tumor microenvironment including hypoxic conditions, glucose restriction, and immune suppression - all of which these cells must overcome to function therapeutically. Although it is known that epigenetic mechanisms play an important role in lymphocyte activation, the mechanisms these cells might use to adapt to the extreme conditions of the solid tumor environment are not well understood. The complete tumor regression rates for adoptive T cell therapy for melanoma are 10-20%; thus, new approaches to combat epigenetic immunomodulation are needed for adoptive cell therapies to reach their full potential. The methyltransferase EZH2 (Enhancer of Zeste Homolog 2) is a histone-modifying enzyme that has been shown to be rapidly induced during lymphocyte activation and a target of glucose deprivation in the melanoma microenvironment. The central hypothesis of this work is that the histone methyltransferase EZH2 protects TILs from metabolic stress-induced apoptosis. The following aims will be used to test this hypothesis: Aim1: Define changes in the histone epigenetic landscape of lymphocytes during EZH2 inhibition. Aim 2: Define the mechanism(s) by which loss of H3K27me3 sensitizes lymphocytes to metabolic stress. Aim 3: Demonstrate the therapeutic potential of EZH2 over-expression in tumor-specific lymphocytes. At the end of this study, I feel strongly that a novel mechanism will be defined for protection of lymphocytes during metabolic stress. Additionally, I intend to devise a novel approach for protecting lymphocytes from metabolic immunosuppression. I have assembled a mentoring team of leaders in epigenetics, cancer immunology, and proteomics that will facilitate this unique and rigorous training, preparing me to pursue a career as an independent academic scientist.

黑色素瘤浸润淋巴细胞中代谢应激途径的表观遗传调节通过检查点抑制释放抗肿瘤淋巴细胞，而收养细胞疗法是令人难以置信的与转移性黑色素瘤作斗争的有前途的策略。 T细胞过养疗法已显示出患者的成功检查点抑制剂疗法失败。收养治疗中的肿瘤浸润淋巴细胞（TIL）面临当遇到肿瘤微环境（包括缺氧条件，葡萄糖限制）时，它们的应力寄托和免疫抑制 - 所有这些细胞都必须克服以治疗功能。虽然是知道表观遗传机制在淋巴细胞激活中起重要作用，这些细胞的机制可能不太了解适应实体瘤环境的极端条件。这黑色素瘤的养育T细胞疗法的完全肿瘤消退率为10-20％；因此，新方法作战表观遗传学免疫调节需要使收养细胞疗法具有全部潜力。这甲基转移酶EZH2（Zeste同源物2的增强子）是一种组蛋白修饰的酶，已显示为已显示为在淋巴细胞激活期间迅速诱导和黑色素瘤中葡萄糖剥夺靶点微环境。这项工作的中心假设是组蛋白甲基转移酶EZH2保护TILS 来自代谢应激诱导的凋亡。以下目的将用于检验以下假设：AIM1：定义 EZH2抑制期间淋巴细胞的组蛋白表观遗传景观的变化。目标2：定义 H3K27me3损失的机制使淋巴细胞敏感到代谢应激。目标3：证明 EZH2在肿瘤特异性淋巴细胞中过表达的治疗潜力。在这项研究结束时，我觉得强烈认为，将在代谢应激期间定义一种新的机制来保护淋巴细胞。此外，我打算设计一种保护淋巴细胞免受代谢免疫抑制的新方法。我已经组建了一支由表观遗传学，癌症免疫学和蛋白质组学领导者组成的指导团队促进这种独特而严格的培训，为我做准备从事独立学术的职业科学家。