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

项目摘要 癌症是世界范围内主要的死亡原因。免疫检查点使用的最新进展 封锁改变了肿瘤学，免疫疗法扩大了 全身疾病的放射治疗。联合检查点封锁和联合治疗的200多项临床试验 放射治疗正在进行或已完成。这些初步试验的结果仅在 有限的病人亚群。治疗耐药可能表现为T细胞启动不良和肿瘤- 介导性免疫抑制继续构成最佳患者结局的重大障碍；因此， 在这种情况下，带来变革性临床影响的机会是真实的。 我们在新发现的指导下提出了一种新的创新战略，以改善 结合新兴的信使核糖核酸领域的最新技术进行放射治疗和免疫治疗 用成熟的放射生物学和免疫学方法进行修饰。我们将利用 与我们的合作调查员川和合作，他帮助发现和破译了可逆的RNA 转录后基因表达调控中的甲基化。我们将使用新的技术来识别 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阅读器对放射肿瘤免疫细胞功能通路的影响。这些技术都是新技术 据我们所知，这些药物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(用于改进的抗原提呈和T细胞启动)和YTHDF2(用于缓解 免疫抑制)将增强抗肿瘤免疫在RT单独和RT联合 抗PD-L1抗体。我们的建议集中在1)建立YTHDF1(目标1)和YTHDF2(目标2)为 RT和放射免疫治疗的可行靶点，以及2)揭示潜在的途径。小分子来自 实验室将被用来验证我们的假设。这种治疗方法的最终目标是 通过靶向m6A甲基化调节基因表达，该甲基化与基因的翻译(Y1)或降解(Y2)相关 信使核糖核酸以增强免疫应答。 我们在发现新知识和阐明前所未有的水平上处于独特的地位 放射治疗与放射治疗之间复杂的分子和细胞相互作用的机制研究 在免疫系统背景下的检查点抑制。这些新的发现将提供机制 翻译追求卓越的治疗策略所需的数据。增强本地和/或远程控制，以 实施放射免疫治疗将是一种改变做法的做法，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池。

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.