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

项目摘要/摘要 检查站封锁彻底改变了癌症免疫治疗领域，但许多肿瘤仍然存在 由于肿瘤微环境中缺乏效应性T细胞的渗透和激活而无反应。先天的 免疫启动这些“冷”肿瘤已经成为一种治疗策略，以提高疗效 通过刺激I型干扰素的产生和下游适应性反应实现检查点阻断。 最近的努力和正在进行的临床试验都集中在激活依赖刺痛的抗病毒途径上。 促进肿瘤微环境中干扰素的产生。然而，许多肿瘤下调了刺痛的表达。 信号转导，而STING激动剂的治疗作用被认为是通过它们对肿瘤的影响而介导的。 渗入宿主髓系细胞。 我们的实验室最近发现，DNA损伤传感器DNA-PK触发了一种非刺激性DNA 人类细胞中的感应通路(SIDSP)，它能有效地激活干扰素的产生，以响应外来DNA。 我们已经开发出依赖DNA-PK的抗病毒免疫的合成超级激动剂，可以触发强大的 人类黑色素瘤细胞对刺痛激动剂无反应的抗病毒反应。我们假设 激活肿瘤细胞内的SIDSP将提供一个独特的信号来增强肿瘤内的炎症 并将激发强大的免疫反应。 这项建议的目标是评估DNA-PK-SIDSP激活作为人类治疗策略 癌症。我们将确定DNA-PK如何对DNA损伤和外来DNA造成不同的结果，我们 将评估在体外和体内触发DNA-PK-SIDSP对人类肿瘤的治疗潜力 使用尖端的人性化老鼠模型。我们的研究将揭示生物学的基本新方面 以及首次对DNA-PK激活作为一种新癌症的临床前评估 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.