Activation of the DNA-PK-dependent antiviral response as a novel cancer immunotherapy

项目概要/摘要 检查点阻断彻底改变了癌症免疫疗法治疗领域，但许多肿瘤仍然存在 由于在肿瘤微环境中缺乏效应T细胞浸润和活化，因此没有反应。先天 这些“冷”肿瘤的免疫引发已经成为一种治疗策略， 通过刺激的I型干扰素（IFN）产生和下游适应性应答阻断检查点。 最近的努力和正在进行的临床试验集中在STING依赖性抗病毒途径的激活上 以促进肿瘤微环境中IFN的产生。然而，许多肿瘤下调STING， STING激动剂的治疗作用被认为是通过它们对肿瘤的作用介导的。 浸润宿主骨髓细胞 我们的实验室最近发现，DNA损伤传感器DNA-PK触发了一种不依赖于STING的DNA 感应途径（SIDSP）在人类细胞中，有效地激活干扰素的生产，以响应外来DNA。 我们已经开发了DNA-PK依赖性抗病毒免疫的合成超激动剂， 在人黑色素瘤细胞中的抗病毒应答对STING激动剂无应答。我们假设 肿瘤细胞内SIDSP的激活将提供独特的信号以增强肿瘤内的炎症 并能激发强有力的免疫反应 本提案的目标是评估DNA-PK-SIDSP激活作为人类中的治疗策略。 癌我们将确定DNA-PK如何指导DNA损伤与外源DNA的不同结果， 将在体外和体内评估触发DNA-PK-SIDSP在人类肿瘤中的治疗潜力 使用最先进的人源化小鼠模型。我们的研究将揭示生物学的基本新方面 以及DNA-PK活化作为一种新型癌症的首次临床前评价 免疫疗法

Project Summary/Abstract Checkpoint blockade has revolutionized the field of cancer immunotherapy treatment, but many tumors remain unresponsive due to lack of effector T cell infiltration and activation in the tumor microenvironment. Innate immune priming of these “cold” tumors has emerged as a therapeutic strategy for increasing the efficacy of checkpoint blockade through stimulated type I interferon (IFN) production and downstream adaptive response. Recent efforts and ongoing clinical trials have focused on activation of the STING-dependent antiviral pathway to promote IFN production in the tumor microenvironment. However, many tumors downregulate STING signaling, and the therapeutic effects of STING agonists are thought to be mediated by their effects on tumor- infiltrating host myeloid cells. Our lab recently discovered that the DNA damage sensor DNA-PK triggers a STING-independent DNA sensing pathway (SIDSP) in human cells that potently activates IFN production in response to foreign DNA. We have developed synthetic superagonists of DNA-PK-dependent antiviral immunity that trigger potent antiviral responses in human melanoma cells that are unresponsive to STING agonists. We hypothesize that activation of the SIDSP within tumor cells will provide a unique signal to enhance inflammation within tumors and will stimulate potent immune responses. The goal of this proposal is to assess DNA-PK-SIDSP activation as a therapeutic strategy in human cancer. We will determine how DNA-PK directs distinct outcomes to DNA damage versus foreign DNA, and we will evaluate the therapeutic potential of triggering the DNA-PK-SIDSP in human tumors, in vitro and in vivo using cutting edge humanized mouse models. Our studies will uncover fundamental new aspects of the biology of the SIDSP, together with the first pre-clinical evaluation of DNA-PK activation as a novel cancer immunotherapy.