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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要癌症免疫疗法利用患者的免疫系统来识别和破坏肿瘤细胞。当前治疗的一个主要挑战是肿瘤微环境的免疫抑制性质限制抗肿瘤免疫反应的效力，克服免疫抑制的新方法是传递刺激先天免疫并将肿瘤转化为免疫激活状态的自然信号促进细胞毒性 T 细胞的浸润和交叉启动。在人类中，cGAS-STING 先天免疫。途径通过检测肿瘤来源的胞质 DNA 并诱导 pro-来控制有效的抗肿瘤反应从机制上讲，DNA 传感会激活 cGAS（环状 GMP-AMP 合酶）。合成核苷酸第二信使2'3'-cGAMP，然后通过环状二核苷酸受体 STING（干扰素基因的 STimulator）从而控制 cGAS-STING 激活。是一种刺激抗肿瘤免疫的令人兴奋的新策略，天然和合成的临床前景。 STING 激动剂强调发现和定义新核苷酸第二功能的重要性可以扩展免疫治疗工具集的信使信号。对于该提案的 F99 阶段，我将描述我的发现，即 cGAS 是一个多样化的大家族的一部分被称为“cGAS 样受体”（cGLR）的免疫传感器未表征的 cGLR 的显着多样性。人类和动物支持先天免疫中许多新的核苷酸信号仍有待发现。研究发现 cGLR1 是果蝇中的 dsRNA 传感器，可通过以下方式控制抗病毒免疫反应：新的核苷酸信号 3'2'-cGAMP，证明 cGLR 酶家族可以感知超越我目前的研究是如何通过不同的核苷酸第二信使来研究双链 DNA 和信号。果蝇 cGLR 通过未表征的核苷酸响应独特的分子模式和信号最终，我的研究构建了一个机制框架来定义新的 cGLR 信号通路。动物和人类，并了解多种核苷酸第二信使在免疫中的作用。对于该提案的 K00 阶段，我将利用我们对核苷酸第二信使的扩展知识使用细菌筛选平台发现刺激抗肿瘤免疫的新分子。向肿瘤传递多种 cGAS 样酶我将识别激活的化学上独特的核苷酸信号作为这个新发现管道的一部分，我将使用体内肿瘤模型和机制。剖析人体细胞中的信号传导以定义新的免疫途径并开发新的免疫疗法我的研究将利用类 cGAS 酶自然产生的化学多样性来扩展。我们用于治疗癌症的免疫学工具集。总之，我的建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。