Targeting ATM to boost systemic effects of radiotherapy and immunotherapy

项目总结 近年来，免疫检查点阻断(ICB)疗法在肿瘤治疗中显示出巨大的应用前景。 然而，目前只有少数患者可以从免疫检查点治疗中受益。 尽管癌症患者的差异反应所涉及的分子机制 免疫检查点治疗仍不清楚，一个普遍的共识是，高水平的肿瘤 突变负担或具有炎症性表型的肿瘤更有可能对免疫产生反应 检查点疗法是由于存在较高数量的抗肿瘤T细胞。因此，它似乎 改进免疫检查点治疗的主要挑战是操纵肿瘤 微环境使其从抗肿瘤T细胞稀少的“冷”变成“热”的T细胞 许多抗肿瘤的T细胞。因为这样的方法和试剂可以增加炎症 “热”的肿瘤微环境备受追捧。另一方面，放射治疗， 它已被用于治疗局部肿瘤，最近被证明可以激活免疫。 信号通路。这些发现增加了一种诱人的可能性，即 通过调节肿瘤免疫微环境，可提高放射治疗效果。 在这个项目中，我们将检验ATM抑制是一种有效的方法的假设 通过下调线粒体生物发生激活cGAS/STING通路使ICB治疗成为可能 增强放射治疗的远景效应。 我们将首先进行实验，以确定自动取款机抑制是否可以显著增强 应用CRISPR介导的ATM基因敲除进行ICB治疗(目标1)。我们还将尝试 定义涉及ATM抑制的下游分子机制和因素- 介导性加强ICB治疗(目标2)。此外，我们将评估一个小分子是否 ATM抑制剂可增强ICB治疗和全身(即非局部性)效应 同基因小鼠肿瘤模型的放射治疗(目标3)。 项目完成后，我们希望能对自动取款机在 抑制细胞天然免疫的激活。这样的理解可能会促进快速 开发新的方法来加强ICB治疗和放射治疗。

PROJECT SUMMARY Immune checkpoint blockade (ICB) therapy has shown great promise in cancer treatment recently. However, currently only a minority of patients could benefit from immune checkpoint therapy. Although the molecular mechanisms involved in the differential responses of cancer patients to immune checkpoint therapy remain unclear, a general consensus is that tumors with high mutational burden or tumors with inflammatory phenotypes are more likely to respond to immune checkpoint therapy due to the presence of higher numbers of anti-tumor T-cells. Thus it appears that the main challenge to improve immune checkpoint therapy is to manipulate the tumor microenvironment so it changes from a “cold” one with few anti-tumor T cells to a “hot” one with many anti-tumor T cells. As such methods and agents that can increase the inflammatory “hotness” of the tumor microenvironment are highly sought after. On the other hand, radiotherapy, which has been used to treat localized tumors, has been recently shown to activate immune signaling pathways. Those discoveries raise the tantalizing possibility that the efficacy of radiotherapy may be enhanced by manipulating the tumor immune microenvironment. In this project, we will examine the hypothesis that ATM inhibition is an effective approach to activate the cGAS/STING pathway by down-regulating mitochondria biogenesis to enable ICB therapy and boosts abscopal effect of radiotherapy. We will initially conduct experiments to determine if ATM inhibition could significantly enhance ICB therapy by use of CRISPR-mediated gene knockout of ATM (Aim 1). We will also attempt to define the downstream molecular mechanisms and factors that are involved ATM inhibition- mediated enhancement of ICB therapy (Aim 2). In addition, we will evaluate if a small molecule inhibitor of ATM could enhance ICB therapy and the systemic (i.e. abscopal) effects of radiotherapy in syngeneic mouse tumor models (Aim 3). Upon completion of the project, we hope we can gain significant insights into the roles of ATM in restraining activation of cellular innate immunity. Such understanding may facilitate the rapid development of novel approaches to enhance ICB therapy and radiotherapy.