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

PGE2 受体抑制抗肿瘤免疫中的 cGAS/STING 反应

• 批准号: 10115611
• 负责人: Darren Perkins
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10115611
• 关键词: Agonist; Animal Cancer Model; Animals; Antitumor Response; Antiviral Agents; Autoimmune; Binding; CD8B1 gene; Cancer cell line; Cells; Clinical Treatment; Clinical Trials; Cyclic Nucleotides; Cytosol; DNA; DNA Binding; Data; Dendritic Cells; Dinoprostone; Disease; Elements; Endoplasmic Reticulum; Feedback; Genetic Transcription; Goals; Homeostasis; Human; Hyperactivity; IRF3 gene; Immune; Immune response; Immune system; Immunologic Surveillance; Immunosuppression; Immunotherapy; Inflammatory; Interferon Type I; Interferon-beta; Interferons; Kinetics; Knowledge; Ligands; Light; Lipids; Literature; Malignant - descriptor; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Mitochondrial DNA; Modeling; Molecular; Mus; Nuclear; Pathology; Pathway interactions; Patients; Pattern recognition receptor; Pharmacologic Substance; Pharmacology; Pre-Clinical Model; Production; Prognosis; Prostaglandin E Receptor; Prostaglandins; Proteins; Regulation; STING agonists; Signal Pathway; Stimulator of Interferon Genes; System; Testing; Therapeutic; Tissues; Tumor Biology; Tumor Burden; Tumor Cell Line; Tumor Immunity; Tumor Tissue; Tumor-associated macrophages; Vascular Diseases; anti-tumor immune response; autocrine; carcinogenesis; cytokine; efficacy testing; extracellular; in vitro Model; in vivo; infancy; interest; lipidomics; macrophage; metaplastic cell transformation; monocyte; paracrine; receptor; response; sensor; transcription factor; tumor; tumor microenvironment

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.

项目总结