Harnessing the innate immunotransmitter cGAMP for anti-cancer therapy

项目摘要 靶向适应性免疫系统的癌症免疫疗法导致先前考虑的癌症治愈。 晚期癌症患者。这一非凡的成就使基础研究人员和临床医生都感到兴奋， 寻找可以治疗更高比例的患者和更多癌症的免疫疗法。我们现在知道 对癌症的有效适应性免疫应答取决于强有力的先天免疫应答，并且 干扰素基因刺激因子（STING）是激发抗癌免疫的主要先天免疫途径。 级联。STING途径上最不了解的分子是第二信使2 '3'-环GMP-AMP （cGAMP），其已被表征为细胞内信号。我们发现cGAMP也是一种 细胞外信号或免疫递质，其激活抗癌先天免疫应答。这项建议 旨在确定这种新型细胞外cGAMP细胞间信号传导的机制，并开发工具， 增强治疗效果 cGAMP由癌细胞输出，它可以由其他细胞输入以激活它们的STING途径。 其细胞外浓度由占优势的cGAMP水解酶外核苷酸调节 焦磷酸酶磷酸二酯酶1（ENPP 1），其是细胞外蛋白。这使ENPP 1在地图上 作为先天免疫检查点。我将通过关注细胞外cGAMP信号传导的机制来探索 通过输出增强细胞外cGAMP和通过ENPP 1抑制细胞外cGAMP 降解具体来说，我将开发一种小分子ENPP 1抑制剂，可用于测试ENPP 1是否是 先天免疫治疗靶点然后，我将确定癌细胞中占主导地位的cGAMP输出机制。 这项研究在基础发现和治疗开发之间架起了桥梁， 产生基本的生物化学基础的支柱，在其上建立新一代的免疫疗法。 在这个项目中，我将建立我的生物化学工具箱，用于解剖免疫系统中的分子机制。 我将培养一种直觉，来提出重要的生物学问题。此外，我将 通过提案，演讲和对话交流我的科学，并将参与指导和 在我的赞助人、共同赞助人和同事的大力支持下， 作为我在斯坦福大学与之建立关系的合作者，我期待着接受培训， 成为化学生物学领域的独立领导者。

PROJECT ABSTRACT Cancer immunotherapy targeting the adaptive immune system results in cures of previously considered terminally ill cancer patients. This remarkable achievement has excited basic researchers and clinicians alike to search for immunotherapies that can treat a higher percentage of patients and more cancers. We now know that an effective adaptive immune response to cancer depends on a robust innate immune response, and that Stimulator of Interferon Genes (STING) is the major innate immune pathway that sparks the anti-cancer immune cascade. The least understood molecule on the STING pathway is the second messenger 2’3’-cyclic GMP-AMP (cGAMP), which has been characterized as an intracellular signal. We discovered that cGAMP is also an extracellular signal, or immunotransmitter, that activates the anti-cancer innate immune response. This proposal aims to determine the mechanism of this novel extracellular cGAMP cell-to-cell signaling and develop tools to enhance it therapeutically. cGAMP is exported by cancer cells, and it can be imported by other cells to activate their STING pathway. Its extracellular concentrations are regulated by the dominant cGAMP hydrolase ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1), which is an extracellular protein. This puts ENPP1 on the map as an innate immune checkpoint. I will probe the mechanism of extracellular cGAMP signaling by focusing on the enhancement of extracellular cGAMP by export and the suppression of extracellular cGAMP by ENPP1 degradation. Specifically, I will develop a small molecule ENPP1 inhibitor that can be used to test if ENPP1 is an innate immunotherapy target. Then, I will identify the dominant cGAMP export mechanism in cancer cells. This research bridges the interface between fundamental discovery and therapeutic development and will generate the pillars of a basic biochemical foundation on which to build new generations of immunotherapies. During this project, I will build my biochemical toolbox for dissecting molecular mechanisms in the immune response to cancer, and I will develop an intuition for asking important biological questions. Furthermore, I will communicate my science via proposals, presentations, and conversations, and will be involved in mentoring and teaching other scientists around me. Supported strongly by my sponsor, co-sponsor, and the colleagues and collaborators with whom I have forged relationships at Stanford University, I look forward to training towards becoming an independent group leader in the field of chemical biology.