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代谢应激途径的表观遗传调控通过检查点抑制和过继细胞疗法释放抗肿瘤淋巴细胞是令人难以置信的对抗转移性黑色素瘤的有前景的策略。 T 细胞过继疗法已在以下患者中取得成功：检查点抑制剂治疗失败。过继治疗中的肿瘤浸润淋巴细胞（TIL）面临着挑战当它们遇到肿瘤微环境时会承受许多压力，包括缺氧条件、葡萄糖限制、和免疫抑制——这些细胞必须克服所有这些才能发挥治疗功能。虽然它是已知表观遗传机制在淋巴细胞激活中发挥重要作用，这些细胞的机制实体瘤可能用于适应极端条件的环境还不太清楚。这黑色素瘤过继性 T 细胞疗法的肿瘤完全消退率为 10-20%；因此，新的方法过继细胞疗法需要对抗表观遗传免疫调节才能充分发挥其潜力。这甲基转移酶 EZH2（Zeste 同源物增强子 2）是一种组蛋白修饰酶，已被证明可以在淋巴细胞激活过程中被快速诱导，并且是黑色素瘤中葡萄糖剥夺的目标微环境。这项工作的中心假设是组蛋白甲基转移酶 EZH2 保护 TIL 来自代谢应激诱导的细胞凋亡。以下目标将用于检验该假设：目标 1：定义 EZH2 抑制期间淋巴细胞组蛋白表观遗传景观的变化。目标 2：定义 H3K27me3 缺失使淋巴细胞对代谢应激敏感的机制。目标 3：展示 EZH2在肿瘤特异性淋巴细胞中过度表达的治疗潜力。学习结束后我的感受是强烈建议将定义一种新的机制来在代谢应激期间保护淋巴细胞。此外，我打算设计一种新方法来保护淋巴细胞免受代谢免疫抑制。我组建了一个由表观遗传学、癌症免疫学和蛋白质组学领域的领导者组成的指导团队，他们将促进这种独特而严格的培训，为我追求独立学者的职业生涯做好准备科学家。