Investigating the tumor-immune interactome in metastases

研究转移中的肿瘤免疫相互作用组

• 批准号: 10305285
• 负责人: Orr-El Weizman
• 金额: $ 4.75万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305285
• 关键词: Ablation; Cell Compartmentation; Cell Line; Cell Separation; Cell Surface Proteins; Cell physiology; Cells; Complex; Cues; Dendritic Cells; Development; Disease; Disease Outcome; Disease Progression; Distal; Fellowship; Growth; Homeostasis; Immune; Immune response; Immune system; Immunity; Immunologic Surveillance; Immunotherapeutic agent; Immunotherapy; Inflammatory; Innate Immune Response; Innate Immune System; Instruction; Interferons; Intervention; Investigation; Knowledge; Lead; Lung; Lymphocyte; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic to; Modeling; Molecular; Mus; Natural Killer Cells; Nature; Neoplasm Metastasis; Patients; Pattern; Phase; Population; Primary Neoplasm; Production; Refractory; Reporter; Research; Role; Sampling; Shapes; Signal Transduction; Site; Source; System; T cell response; T-Lymphocyte; Techniques; Technology; Therapeutic; Tissues; Training; base; cancer cell; cell transformation; cytokine; immunogenic; improved; in vivo; innate immune sensing; insight; lung metastatic; melanoma; neoplastic cell; new technology; notch protein; novel; pathogen; programs; response; sensor; synthetic biology; tool; treatment response; tumor; tumor immunology

PROJECT SUMMARY The progression of transformed primary tumors to metastatic colonization is a lethal determinant of disease outcome. While the immune system actively engages with metastatic cells in both supportive and limiting roles, the functional consequence of the tumor – immune interactome (the entirety of interactions between immune cells and tumor cells) during metastatic disease remains ill defined. In the F99 portion of this proposal we will examine how local immune cells orchestrate host anti-metastatic immunity. While circulating adaptive and innate lymphocyte effector responses are required for effective anti- metastatic immunity, whether tissue resident immune circuits confer initial immunity at sites of metastatic dissemination remains to be elucidated. Using a syngeneic mouse melanoma model, we have demonstrated that lung resident conventional type 2 dendritic cells (DC2) orchestrate local immune circuits to confer initial host anti-metastatic immunity. Specific ablation of lung DC2, and not peripheral DC populations, led to increased metastatic burden in the presence of an intact T cell and NK cell compartment. Critically, DC2 serve as a robust source of proinflammatory cytokines that directs the essential local production of IFN- by lung resident NK cells. Collectively our results highlight a novel DC2 - NK cell axis that colocalizes around pioneering metastatic cells in order to orchestrate a non-redundant innate immune response program to limit initial metastatic burden in the lung. In Aim 1 we will explore the signals that activate DC2 controlled immune circuits and elucidate the mechanism that instruct both immediate and long term adaptive anti-metastatic immunity. Ultimately, we will look to see how we can leverage this knowledge to potentiate host-anti-metastatic responses in immune refractory tumors. In the K00 phase of this proposal, I propose to extend my research of investigating immune interactions during metastasis by developing a novel in vivo tool to discover and record the tumor-immune interactome. The ability of immune cells to directly interact with transformed cell is an essential component of immune surveillance of the tissue and critical for optimal function. However, the nature and consequence of immune surveillance in the metastatic microenvironment remains unclear. Current tools are limited in their ability to faithfully record and discover novel interactors in vivo. In Aim 2, we plan to develop, validate, and apply a novel technology to discover and record the tumor immune interactome in an unbiased way using Synthetic Notch receptors. This system, which we call Tumor Immune Interactome Non-biased Discovery Reporter (TIINDR), will allow us to interrogate immune interactors and non-interactors in metastatic tumor models in order to understand that nature and consequence of metastatic immunosurveillance. Collectively, this proposed research will provide insights into the mechanism of immune surveillance and identify novel and actionable targets for improved immunotherapeutic strategies for treating metastatic disease.

项目摘要 转化的原发性肿瘤向转移性定殖的进展是疾病的致命决定 结果。虽然免疫系统在支持和限制角色中都积极与转移细胞接合，但 肿瘤 - 免疫相互作用组的功能后果（免疫之间的整体相互作用 转移性疾病期间的细胞和肿瘤细胞）仍然不明显。 在该提案的F99部分中，我们将研究局部免疫细胞如何编排宿主抗转移性 免疫。虽然需要循环适应性和先天淋巴细胞效应子反应才能有效抗 转移性免疫，组织居民免疫电路是否会在转移性部位进行初始免疫力 传播仍有待阐明。使用合成小鼠黑色素瘤模型，我们已经证明了 肺居民常规2型树突状细胞（DC2）将局部免疫电路策划至会议初始电路 宿主抗转移性免疫。肺DC2的特定消融，而不是周围DC种群，导致 在完整的T细胞和NK细胞室的存在下，转移性燃烧增加。至关重要的是，DC2服务 作为促炎细胞因子的强大来源，该因子指导肺的基本局部生产 居民NK细胞。我们的结果集体强调了一个新型的DC2 -NK细胞轴，该轴围绕着围绕 开创性转移细胞为了协调非冗余的先天免疫响应计划以限制 肺中的初始转移燃烧。在AIM 1中，我们将探索激活DC2受控免疫的信号 电路并阐明了指导立即和长期自适应抗中型的机制 免疫。最终，我们将研究如何利用这一知识到潜在的host-anti-Metanscatic 免疫治疗肿瘤的反应。 在本提案的K00阶段，我提出了扩展有关调查免疫相互作用的研究 在转移过程中，通过开发一种新型的体内工具来发现和记录肿瘤免疫相互作用组。 免疫细胞直接与转化细胞相互作用的能力是免疫的重要组成部分 组织的监视，对于最佳功能至关重要。但是，免疫的性质和后果 转移微环境中的监视尚不清楚。当前工具的能力有限 忠实地记录并发现体内新颖的互动者。在AIM 2中，我们计划开发，验证和应用小说 使用合成缺口以公正的方式发现和记录肿瘤免疫相互作用的技术 接收者。这个系统，我们称之为肿瘤免疫相互作用的非偏置发现报告基因（TIINDR）， 将使我们能够在转移性肿瘤模型中询问免疫相互作用者和非相互作用者 了解转移性免疫监视的性质和后果。 总的来说，这项拟议的研究将提供有关免疫监视机制和 确定新的和可行的靶标，以改善治疗转移性疾病的免疫治疗策略。