Investigating the tumor-immune interactome in metastases

项目摘要 转化的原发性肿瘤向转移性定植的进展是疾病的致命决定因素 结果。虽然免疫系统在支持和限制作用中积极地与转移细胞接合， 肿瘤-免疫相互作用组的功能结果（免疫细胞之间的全部相互作用）是肿瘤-免疫系统相互作用的结果。 细胞和肿瘤细胞）仍然不清楚。 在本提案的F99部分，我们将研究局部免疫细胞如何协调宿主抗转移 免疫力虽然循环适应性和先天性淋巴细胞效应器反应是有效的抗肿瘤所必需的， 转移性免疫，组织固有免疫回路是否在转移性免疫部位赋予初始免疫， 传播仍有待澄清。使用同基因小鼠黑色素瘤模型，我们已经证明 肺驻留的传统2型树突状细胞（DC 2）协调局部免疫回路， 宿主抗转移免疫。特异性消融肺DC 2，而不是外周DC群，导致 在存在完整T细胞和NK细胞区室的情况下，转移负荷增加。关键是，DC 2服务于 作为促炎细胞因子的强大来源，其指导肺局部产生IFN-γ的必要性。 NK细胞。总的来说，我们的结果突出了一种新的DC 2- NK细胞轴， 开拓转移细胞，以协调非冗余的先天免疫反应程序， 肺部的初始转移负担。在目标1中，我们将探索激活DC 2控制的免疫的信号。 电路和阐明机制，指导立即和长期适应性抗转移 免疫力最终，我们将看看我们如何利用这些知识来增强宿主抗转移的能力。 免疫难治性肿瘤的反应。 在本提案的K 00阶段，我建议扩展我对免疫相互作用的研究 通过开发一种新的体内工具来发现和记录肿瘤-免疫相互作用组， 免疫细胞与转化细胞直接相互作用的能力是免疫调节的重要组成部分。 对组织的监视和对最佳功能的关键。然而，免疫的性质和后果 转移微环境中的监测仍不清楚。目前的工具在以下方面的能力有限： 忠实地记录和发现新的互动在体内。在目标2中，我们计划开发、验证和应用一种新的 使用合成缺口技术以公正的方式发现和记录肿瘤免疫相互作用组的技术 受体。这个系统，我们称之为肿瘤免疫相互作用组非偏倚发现报告（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性质和后果。 总的来说，这项拟议中的研究将提供对免疫监视机制的见解， 鉴定用于治疗转移性疾病的改进的免疫策略的新的和可操作的靶标。

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.