PGE2 Receptor Suppression of cGAS/STING Responses in anti-tumor immunity

项目摘要 肿瘤微环境(TME)中炎性信号的强度是决定肿瘤预后的关键因素 宿主抗肿瘤免疫反应。I型干扰素由肿瘤组织直接产生或由肿瘤产生 相关巨噬细胞和树突状细胞可增加TME的炎症潜能 显著增加自发细胞介导的抗肿瘤反应(如CD8T和NK)。CGAS/STING 先天免疫传感器系统最近被发现是TME中产生干扰素的主要驱动因素 这引起了人们对cGAS/STIN单独的药理刺激和对 与其他免疫疗法相结合。然而，肿瘤如何逃避或最小化cGAS/刺痛 对激动剂的反应是一个悬而未决的问题。我们发现cGAS/STING的激活物 Axis触发一致的前列腺素PGE2反应，有效抑制刺痛依赖的干扰素 通过特定的EP3受体产生。这种PGE2自分泌/旁分泌负反馈环可能 限制从肿瘤组织本身和从肿瘤产生cGAS/Sting干扰素的程度的功能 相关的先天免疫细胞。鉴于广泛的肿瘤，这一初步观察也值得注意。 生物学文献表明，许多类型的肿瘤可以结构性地分泌高水平的PGE2，从而 与肿瘤侵袭性和患者预后不良有关。肿瘤的这种有害影响 PGE2的分泌可能部分是由于cGAS/STIN抑制了天然免疫监视。整体而言 本项目的目标是了解在cGAS/STING反应过程中PGE2的产生机制 并确定抑制PGE2受体EP3是否有助于肿瘤的控制 活体临床前模型。在目标1中，我们将定义在初级免疫中控制PGE2产生的途径 细胞和肿瘤细胞系，并确定PGE2/EP3对cGAS/STIN的调节是否是共同特征 来自多种组织类型的肿瘤。在AIM2中，我们将使用已建立的动物肿瘤模型来测试其疗效 药物抑制PGE2/EP3反馈通路对cGAS/STIN激活和干扰素应答的影响 TME。

Project Summary The strength of the inflammatory signature in the tumor microenvironment (TME) is a critical determinant of the host anti-tumor immune response. Type I Interferon (IFN) production by tumor tissue directly or by tumor associated macrophages and dendritic cells can increase the inflammatory potential of the TME and significantly increase spontaneous cell mediated anti-tumor responses (e.g. CD8 T and NK). The cGAS/STING innate immune sensor system has recently been uncovered as a major driver of IFN production in the TME and this has generated considerable interest in pharmacologic stimulation of cGAS/STING alone and in conjunction with other immuno-therapies. However, how tumors may evade or minimize cGAS/STING responses in response to agonists is an open question. We have found that activators of the cGAS/STING axis trigger a coincident prostaglandin PGE2 response which potently suppresses STING dependent IFN production through the specific EP3 receptor. This PGE2 autocrine/paracrine negative feedback loop likely functions to limit the extent of cGAS/STING IFN production both from the tumor tissue itself, and from tumor associated innate immune cells. This preliminary observation is also notable in light of an extensive tumor biology literature demonstrating that numerous tumor types can constitutively secrete high levels of PGE2 that is associated with tumor aggressiveness and poor patient prognosis. Such deleterious effects of tumor secreted PGE2 may be due in part to suppression of innate immune surveillance by cGAS/STING. The overall goal of this project is to understand the mechanism of PGE2 production during cGAS/STING responses in tumors, and to determine whether inhibition of one PGE2 receptor, EP3, can contribute to tumor control in in vivo pre clinical models. In AIM 1 we will define the pathways governing PGE2 production in primary immune cells and tumor cell lines and ascertain whether regulation of cGAS/STING by PGE2 /EP3 is a common feature of tumors from multiple tissue types. In AIM2 we will use established animal tumor models to test the efficacy of pharmacologically inhibiting the PGE2/EP3 feedback circuit on cGAS/STING activation and IFN responses in the TME.