Elucidating the Roles of RNA m6A readers Y1 and Y2 in radiation-induced immunity and immunotherapy

阐明 RNA m6A 阅读器 Y1 和 Y2 在辐射诱导免疫和免疫治疗中的作用

基本信息

批准号：
10279950
负责人：
RALPH R WEICHSELBAUM
金额：
$ 41.27万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10279950
关键词：
Address Antigen Presentation Antigens Binding Binding Proteins Binding Sites Bioinformatics Biology Cathepsins Cause of Death Cell Culture Techniques Cell Differentiation process Cell physiology Cells Cellular Immunity Clinical Clinical Trials Collaborations Complex Data Dendritic Cells Dendritic cell activation Development Disease Disseminated Malignant Neoplasm Distant Effectiveness Epithelial Future Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Immune Immune response Immune system Immunity Immunologics Immunosuppression Immunotherapy Infiltration Irradiated tumor Knowledge Lead Locally Advanced Malignant Neoplasm Malignant Neoplasms Mediating Mediation Messenger RNA Methods Methylation Modification Molecular Myelogenous Myeloid Cells Natural Immunity Neoplasm Metastasis Oncology PD-1/PD-L1 Pathway interactions Patient-Focused Outcomes Patients Play Positioning Attribute Property RNA RNA methylation Radiation Radiation therapy Radioimmunotherapy Reader Regulation Reporting Research Research Personnel Role Site Solid Neoplasm Specificity Systemic disease T cell response T-Cell Activation T-Lymphocyte Targeted Radiotherapy Techniques Testing Therapeutic Therapeutic Effect Time Translations Tumor Immunity Tumor-infiltrating immune cells adaptive immunity anti-PD-L1 anti-PD-L1 antibodies antigen processing antitumor effect cancer care cancer therapy checkpoint inhibition cytotoxic CD8 T cells experimental study immune checkpoint blockade immunoregulation improved inhibitor/antagonist innovation loss of function migration monocyte novel novel strategies patient subsets pre-clinical prototype response screening small molecule therapy resistant transcriptome sequencing treatment strategy tumor tumor microenvironment

项目摘要

Project Summary Cancer is a leading cause of death worldwide. Recent advancements in the use of immune checkpoint blockade have transformed oncology, and immunotherapy has extended the potential application of radiotherapy to systemic disease. More than 200 clinical trials of combined checkpoint blockade and radiotherapy are ongoing or completed. The results of these preliminary trials demonstrate efficacy only in a limited subpopulation of patients. Treatment resistance likely manifested by poor T-cell priming and tumor- mediated immunosuppression continue to constitute significant barriers to optimal patient outcomes; therefore, the opportunity for transformative clinical impact is real in this setting. We propose a new and innovative strategy guided by new findings to improve the interaction of radiotherapy and immunotherapy by incorporating the latest techniques in the emerging field of mRNA modification with well-established radiobiological and immunological approaches. We will leverage collaboration with our Co-Investigator Chuan He, who helped to discover and decipher reversible RNA methylation in post-transcriptional gene expression regulation. We will use the novel techniques to identify the binding sites of Y1 and Y2, and incorporate integrated bioinformatics analysis approaches to investigate the impact of m6A readers in functional pathways of immune cells in irradiated tumors. These techniques are new and, to our knowledge, have yet to be applied in the context of radiotherapy and radioimmunotherapy. We hypothesize that targeting regulation of m6A modifications associated with m6A-binding protein YTHDF1 (for improved antigen presentation and T-cell priming) and YTHDF2 (for alleviation of immunosuppression) will potentiate anti-tumor immunity in the context of both RT alone and RT combined with anti-PD-L1 antibodies. Our proposal focuses on 1) establishing YTHDF1 (Aim 1) and YTHDF2 (Aim 2) as viable targets for RT and radioimmunotherapy, and 2) uncovering underlying pathways. Small molecules from the He Lab will be used to validate our hypothesis. The ultimate goal of this therapeutic approach is to modulate gene expression via targeting m6A methylation related to translation (Y1) or degradation (Y2) of mRNA in order to potentiate immune response. We are uniquely positioned to discover new knowledge and elucidate an unprecedented level of mechanistic understanding of the complex molecular and cellular interplay between radiotherapy and checkpoint inhibition in the context of the immune system. These new findings will provide the mechanistic data required for translational pursuit of superior treatment strategies. Increased local and/or distant control to actualize radio-immunotherapy would be a practice-changing and would broadly enhance cancer care and expand the pool of patients who respond to inhibition of the PD-1/PD-L1 axis.

项目概要癌症是全世界死亡的主要原因。免疫检查点应用的最新进展封锁改变了肿瘤学，免疫疗法扩展了其潜在应用全身性疾病的放射治疗。超过 200 项检查点封锁联合临床试验放射治疗正在进行或已完成。这些初步试验的结果表明仅在以下情况下有效：有限的患者亚群。治疗抵抗可能表现为 T 细胞启动不良和肿瘤介导的免疫抑制仍然对患者获得最佳治疗结果构成重大障碍；所以，在这种情况下，产生变革性临床影响的机会是真实存在的。我们提出了一项以新发现为指导的新的创新战略，以改善结合 mRNA 新兴领域的最新技术进行放射治疗和免疫治疗使用完善的放射生物学和免疫学方法进行修饰。我们将利用与我们的联合研究员 Chuan He 合作，他帮助发现和破译了可逆 RNA 转录后基因表达调控中的甲基化。我们将使用新颖的技术来识别 Y1 和 Y2 的结合位点，并结合综合生物信息学分析方法来研究 m6A 阅读器对受辐射肿瘤中免疫细胞功能途径的影响。这些技术都是新的据我们所知，尚未应用于放射治疗和放射免疫治疗。我们假设与 m6A 结合蛋白相关的 m6A 修饰的靶向调节 YTHDF1（用于改善抗原呈递和 T 细胞启动）和 YTHDF2（用于减轻免疫抑制）将在单独放疗和放疗联合放疗的情况下增强抗肿瘤免疫力抗 PD-L1 抗体。我们的建议重点是 1) 建立 YTHDF1（目标 1）和 YTHDF2（目标 2）作为放疗和放射免疫治疗的可行目标，2) 揭示潜在的途径。小分子来自 He 实验室将用于验证我们的假设。这种治疗方法的最终目标是通过靶向与翻译 (Y1) 或降解 (Y2) 相关的 m6A 甲基化来调节基因表达 mRNA以增强免疫反应。我们处于独特的地位，能够发现新知识并阐明前所未有的水平对放疗和放疗之间复杂的分子和细胞相互作用的机制理解免疫系统中的检查点抑制。这些新发现将提供机制转化追求卓越治疗策略所需的数据。增加本地和/或远程控制意识到放射免疫疗法将改变实践，并将广泛加强癌症护理和扩大对 PD-1/PD-L1 轴抑制有反应的患者群体。