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

项目摘要 肿瘤微环境（TME）中炎症信号的强度是肿瘤微环境（TME）中炎症反应的关键决定因素。 宿主抗肿瘤免疫应答。I型干扰素（IFN）直接由肿瘤组织或由肿瘤组织产生 相关的巨噬细胞和树突状细胞可以增加TME的炎症潜能， 显著增加自发性细胞介导的抗肿瘤应答（例如CD 8 T和NK）。cGAS/STING 最近发现先天免疫传感器系统是TME中IFN产生的主要驱动力 并且这已经在单独的cGAS/STING的药理学刺激和在 与其他免疫疗法相结合。然而，肿瘤如何逃避或最小化cGAS/STING 对激动剂的反应是一个悬而未决的问题。我们已经发现，cGAS/STING的激活剂 轴触发同时发生的前列腺素PGE 2反应，其有效地抑制STING依赖性IFN 通过特定的EP 3受体产生。这种PGE 2自分泌/旁分泌负反馈回路可能 其功能是限制cGAS/STING IFN从肿瘤组织本身和从肿瘤细胞产生的程度。 相关的先天免疫细胞。这一初步观察也是值得注意的，在光的广泛肿瘤 生物学文献表明，许多肿瘤类型可以组成性分泌高水平的PGE 2， 与肿瘤侵袭性和患者预后不良有关。肿瘤的这种有害影响 分泌的PGE 2可能部分是由于cGAS/STING对先天免疫监视的抑制。整体 该项目的目标是了解在cGAS/STING反应期间PGE 2产生的机制， 肿瘤，并确定是否抑制一种PGE 2受体，EP 3，可以有助于肿瘤控制， 体内临床前模型。在AIM 1中，我们将定义原发性免疫中PGE 2产生的调控途径。 细胞和肿瘤细胞系，并确定PGE 2/EP 3对cGAS/STING的调节是否是共同特征 多种组织类型的肿瘤在AIM 2中，我们将使用已建立的动物肿瘤模型来测试 在cGAS/STING激活和IFN应答中， 的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.