Delineating how nucleic acid sensing in tumor cells regulate anti-tumor immune responses

项目摘要 DNA损伤反应受损可导致癌症的基因组和染色体不稳定。高水平的 染色体不稳定与突变率增加、转移和免疫逃避有关。 在癌症中。然而，矛盾的是，破坏DNA的化疗和放射疗法可以触发抗肿瘤 炎症反应。肿瘤细胞DNA损伤如何调节抗肿瘤和促肿瘤免疫反应 肿瘤内微环境(TME)代表着一个重要的知识鸿沟。格林伯格集团 (项目1)已经表明，癌细胞中的DNA损伤激活了胞浆DNA传感通路，受 环状AMP-GMP合成酶(CGAS)和干扰素基因刺激物(STIN)，以及RNA传感 视黄酸诱导基因I(RIG-I)调控的通路。这些核酸传感模式的激活 识别受体(PRRs)诱导型干扰素(IFN-I)--一种促进保护性免疫的细胞因子 对抗病原体。胞浆核酸还可以激活炎性小体分泌白细胞介素1β和- 18，具有促肿瘤和抗肿瘤作用。有趣的是，我们的初步数据显示炎症小体 在卵巢癌模型中，对DNA损伤的反应激活促进了肿瘤的生长。抗原呈递 细胞(APC)是免疫反应的关键介质，我们最近的工作发现了APC的新亚群 以及它们在TME中受干扰素的调节。在这个提案中，我们将检验这样一个假设，即结果 肿瘤控制的机制是由干扰素-I和IL-1β/IL-18对APC相反的抗肿瘤和促肿瘤作用驱动的 对癌细胞DNA损伤的反应。为了实现这一目标，我们将与项目1密切合作(格林伯格) 和2(Lampson/Discher)，并依赖于新的遗传(MAC核心)和化学(化学生物学核心)工具。 这三个特定的目标将研究依赖干扰素I抗肿瘤的潜在机制(目标1)和 炎症体依赖性促肿瘤(AIM 2)对癌细胞DNA损伤的影响，并提供概念验证 以这些途径为靶点进行组合免疫治疗(目标3)。这些发现将为我们提供基本的 洞察基因组不稳定性如何调节肿瘤免疫反应的免疫机制 为未来针对癌症治疗的这些途径的尝试提供了基础。

Project Summary Impaired DNA damage responses can lead to genomic and chromosomal instability in cancer. High levels of chromosomal instability have been associated with increased mutation rates, metastasis, and immune evasion in cancer. Paradoxically however, DNA- damaging chemo- and radio-therapies can trigger anti-tumor inflammatory responses. How DNA damage in tumor cells regulate both anti-and pro-tumor immune responses within the tumor microenvironment (TME) represents an important knowledge gap. The Greenberg group (Project 1) has shown that DNA damage in cancer cells activate cytosolic DNA sensing pathway regulated by cyclic AMP-GMP synthase (cGAS) and stimulator of interferon genes (STING), as well as an RNA sensing pathway regulated by retinoic acid-inducible gene I (RIG-I). Activation of these nucleic acid-sensing pattern recognition receptors (PRRs) induces type I interferon (IFN-I) – a cytokine that promotes protective immunity against pathogens. Cytosolic nucleic acids can also activate inflammasomes to secrete interleukin (IL)-1β and - 18, which have both pro- and anti-tumor effects. Intriguingly, our preliminary data suggest that inflammasome activation in response to DNA damage promotes tumor growth in an ovarian cancer model. Antigen presenting cells (APCs) are key mediators of immune responses and our recent work have identified novel subsets of APCs and their regulation by interferons in the TME. In this proposal, we will examine the hypothesis that the outcome of tumor control is driven by the opposing anti- and pro-tumor effects of IFN-I and IL-1β/ IL-18 on APCs in response to cancer cell DNA damage. Towards this goal, we will closely collaborate with Projects 1 (Greenberg) and 2 (Lampson/Discher) and rely on novel genetic (MAC core) and chemical (Chemical Biology Core) tools. The three specific aims will examine the mechanisms underlying IFN-I-dependent anti-tumor (Aim 1) and inflammasome dependent pro-tumor (Aim 2) effects of cancer cell DNA damage, and provide proof-of-concept for targeting these pathways for combinatorial immunotherapy (Aim 3). These findings will provide fundamental insights into immune mechanisms underlying how genome instability regulates immune responses in tumor and provide a foundation for future attempts to target these pathways for cancer therapy.