Discovery of diverse nucleotide immune signals for use as novel immunotherapies

发现多种核苷酸免疫信号用作新型免疫疗法

• 批准号: 10528579
• 负责人: Kailey Slavik
• 金额: $ 3.61万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528579
• 关键词: Address; Agonist; Animals; Antigen-Presenting Cells; Antigens; Antitumor Response; Bacteria; Bacteriophages; Biochemical; Biochemistry; Biology; Cancer Control; Cell Culture Techniques; Cells; Chemicals; Clinical; Cross-Priming; Crystallization; Cyclic GMP; Cytotoxic T-Lymphocytes; DNA; Data; Detection; Development; Dinucleoside Phosphates; Dissection; Double-Stranded RNA; Drosophila genus; Enzymes; Escherichia coli; Exhibits; Family; Family member; Human; Immune; Immune response; Immune signaling; Immune system; Immunity; Immunologics; Immunosuppression; Immunotherapy; In Vitro; Infiltration; Inflammatory; Isomerism; Knowledge; Ligand Binding; Ligands; Malignant Neoplasms; Modeling; Molecular; Names; Natural Immunity; Nature; Nucleotides; Pathway interactions; Patients; Pattern; Periodicity; Phagocytes; Phase; Protein Family; Proteins; RNA; Receptor Signaling; Research; Research Project Grants; Research Proposals; Role; STING agonists; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Protein; Stimulator of Interferon Genes; Structure; Sum; Surface; T cell response; Techniques; Therapeutic; Tumor Immunity; Tumor-Derived; Virus Diseases; Work; anti-tumor immune response; base; cancer immunotherapy; design; ds-DNA; experimental study; extracellular; fly; improved; in vivo; innate immune pathways; neoplastic cell; novel; novel strategies; nucleotide receptor; pathogen; receptor; receptor function; recruit; response; screening; sensor; structural biology; success; tool; tumor; tumor growth; tumor microenvironment

Project Summary Cancer immunotherapy leverages a patient’s immune system to recognize and destroy tumor cells. However, a major challenge to current therapeutics is the immunosuppressive nature of the tumor microenvironment that limits the potency of antitumor immune responses. A new approach for overcoming immunosuppression is the delivery of natural signals that stimulate innate immunity and transform tumors into an immunoactivated state to promote the infiltration and cross-priming of cytotoxic T-cells. In humans, the cGAS-STING innate immune pathway controls a potent antitumor response by detecting tumor-derived cytosolic DNA and inducing pro- inflammatory signaling. Mechanistically, DNA sensing activates the enzyme cGAS (cyclic GMP-AMP synthase) to synthesize the nucleotide second messenger 2′3′-cGAMP which then induces immune signaling through the cyclic dinucleotide receptor STING (STimulator of INterferon Genes). Thus, controlling cGAS-STING activation is an exciting new strategy for stimulating antitumor immunity. The clinical promise of natural and synthetic STING agonists underscores the importance of discovering and defining the function of novel nucleotide second messenger signals that can expand the immunotherapy toolset. For the F99 phase of this proposal, I will describe my discovery that cGAS is part of a large family of diverse immune sensors named “cGAS-like receptors” (cGLRs). The remarkable diversity of uncharacterized cGLRs in humans and animals supports that many new nucleotide signals in innate immunity remain to be discovered. My research identified cGLR1 as a dsRNA sensor in Drosophila that controls an antiviral immune response through the novel nucleotide signal 3′2′-cGAMP, demonstrating that the cGLR enzyme family can sense ligands beyond dsDNA and signal through distinct nucleotide second messengers. My current research investigates how a new Drosophila cGLR responds to a unique molecular pattern and signals through an uncharacterized nucleotide messenger. Ultimately, my research builds a mechanistic framework to define new cGLR signaling pathways in animals and humans and understand the role of diverse nucleotide second messengers in immunity. For the K00 phase of this proposal, I will leverage our expanded knowledge of nucleotide second messenger signaling to discover new molecules that stimulate antitumor immunity. Using a bacterial screening platform to deliver diverse cGAS-like enzymes to tumors I will identify chemically unique nucleotide signals that activate human innate immunity. As part of this new discovery pipeline, I will use in vivo tumor models and a mechanistic dissection of signaling in human cells to define new immune pathways and develop novel immunotherapy strategies. My research will harness the chemical diversity naturally generated by cGAS-like enzymes to expand our immunological toolset for treating cancers. In sum, my proposal will define new animal immune signaling pathways and discover novel antitumor molecules as tools for cancer immunotherapy.

项目摘要 癌症免疫疗法利用患者的免疫系统识别和摧毁肿瘤细胞。然而， 当前治疗方法面临的一个主要挑战是肿瘤微环境的免疫抑制性质，即 限制抗肿瘤免疫反应的效力。克服免疫抑制的一种新方法是 传递自然信号，刺激先天免疫并将肿瘤转变为免疫激活状态 促进细胞毒T细胞的渗透和交叉激发。在人类中，cGAS刺痛的先天免疫 通路通过检测肿瘤来源的胞浆DNA并诱导亲肿瘤反应来控制强大的抗肿瘤反应。 炎症信号。从机制上讲，DNA传感激活了cGAS(环状GMP-AMP合成酶) 合成核苷酸第二信使2‘3’-cGAMP，然后通过 环二核苷酸受体刺激物(干扰素基因刺激物)。因此，控制cGAS-STING激活 是一种刺激抗肿瘤免疫的令人兴奋的新策略。天然和人工合成的临床前景 STING激动剂强调了发现和定义新的核苷酸第二功能的重要性 信使信号可以扩展免疫治疗工具包。 对于这项提案的F99阶段，我将描述我的发现，即cGAS是一个不同的 免疫感受器命名为“cGAS样受体”(CGLRs)。未鉴定的cGLRs的显著多样性 人类和动物支持先天免疫中的许多新的核苷酸信号仍有待发现。我的 研究发现，cGLR1是果蝇体内的dsRNA传感器，通过 新的核苷酸信号3‘2’-cGAMP，表明cGLR酶家族可以感知更多的配体 DsDNA和信号通过不同的核苷酸第二信使。我目前的研究调查了一个新的 果蝇cGLR通过一个未知的核苷酸对一种独特的分子模式和信号作出反应 信使。最终，我的研究建立了一个机制框架来定义新的cGLR信号通路 并了解不同的核苷酸第二信使在免疫中的作用。 对于本提案的K00阶段，我将利用我们对核苷酸第二信使的扩展知识 发出信号，发现刺激抗肿瘤免疫的新分子。使用细菌筛选平台 向肿瘤传递不同的cGAS样酶我将识别化学上独特的核苷酸信号 人类的先天免疫力。作为这个新发现管道的一部分，我将使用体内肿瘤模型和一种机械 剖析人类细胞中的信号以确定新的免疫途径和开发新的免疫疗法 战略。我的研究将利用cGAS样酶自然产生的化学多样性来扩大 我们治疗癌症的免疫学工具箱。 总之，我的提议将定义新的动物免疫信号通路，并发现新的抗肿瘤药物 分子作为癌症免疫治疗的工具。