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

项目摘要 癌症是世界范围内的主要死亡原因。免疫检查点使用的最新进展 阻断已经改变了肿瘤学，免疫治疗已经扩展了 全身性疾病的放射治疗。200多项联合检查点阻断和 放射治疗正在进行或已完成。这些初步试验的结果表明，只有在一个 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- 介导的免疫抑制继续构成最佳患者结果的显著障碍;因此， 在这种情况下，产生变革性临床影响的机会是真实的。 我们提出了一个新的和创新的战略指导下的新发现，以改善互动的 放射治疗和免疫治疗，结合mRNA新兴领域的最新技术， 用成熟的放射生物学和免疫学方法进行修饰。我们将利用 与我们的合作研究员Chuan He合作，他帮助发现和破译了可逆RNA 甲基化在转录后基因表达调控中的作用。我们将使用新的技术来识别 结合位点的Y1和Y2，并纳入整合的生物信息学分析方法，以调查 m6 A阅读器在辐射肿瘤中免疫细胞功能途径中的影响。这些技术是新的 并且据我们所知，尚未应用于放射治疗和放射免疫治疗。 我们假设，靶向调节m6 A修饰与m6 A结合蛋白相关， YTHDF 1（用于改善抗原呈递和T细胞引发）和YTHDF 2（用于缓解 免疫抑制）将在单独的RT和RT联合的情况下增强抗肿瘤免疫力。 抗PD-L1抗体。我们的建议集中于1）设立YTHDF 1（目标1）和YTHDF 2（目标2）， RT和放射免疫治疗的可行靶点，以及2）揭示潜在途径。小分子从 氦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m6 A甲基化来调节基因表达，所述甲基化与以下物质的翻译（Y1）或降解（Y2）相关： mRNA以增强免疫反应。 我们处于独特的地位，可以发现新的知识，并阐明前所未有的水平， 对放射治疗和肿瘤治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 转化追求上级治疗策略所需的数据。增加本地和/或远程控制， 实现放射免疫疗法将是一种改变实践的方法，并将广泛加强癌症护理， 扩大对PD-1/PD-L1轴抑制有反应的患者库。

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.