Investigating the tumor-immune interactome in metastases

项目总结 转化的原发肿瘤向转移性定植的进展是疾病的致命决定因素 结果。虽然免疫系统积极地与转移细胞接触，发挥支持和限制的作用， 肿瘤-免疫相互作用体的功能后果(免疫之间相互作用的整体 细胞和肿瘤细胞)在转移性疾病期间的定义仍然不明确。 在这项提案的F99部分，我们将研究局部免疫细胞如何协调宿主抗转移 豁免权。而循环适应性和先天淋巴细胞效应性反应则需要有效的抗病毒作用。 转移免疫--组织驻留免疫回路是否在转移部位给予初始免疫 传播情况仍有待澄清。使用同基因小鼠黑色素瘤模型，我们已经证明 肺常驻常规2型树突状细胞(DC2)协调局部免疫回路以授予初始 宿主抗转移免疫。肺DC2而不是外周树突状细胞群的特异性消融导致 在存在完整的T细胞和NK细胞的情况下，转移负荷增加。关键是，DC2发球 作为促炎细胞因子的强健来源，引导肺局部产生基本的干扰素- 常驻NK细胞。总而言之，我们的结果突出了一个新的DC2-NK细胞轴，它共同定位于 开创转移细胞的先河，以协调非冗余的先天性免疫反应程序，以限制 肺部的初始转移负荷。在目标1中，我们将探索激活DC2受控免疫的信号 并阐明指导即刻和长期适应性抗转移的机制 豁免权。最终，我们将看看如何利用这一知识来增强宿主抗转移能力。 免疫难治性肿瘤的反应。 在这个提案的K00阶段，我建议扩展我对免疫相互作用的研究 在转移过程中，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的重要组成部分 对组织的监视，对最佳功能至关重要。然而，免疫的性质和后果 对转移的微环境的监测仍然不清楚。目前的工具在以下方面的能力有限 忠实地记录和发现体内新的相互作用因素。在目标2中，我们计划开发、验证和应用一种 利用合成Notch无偏地发现和记录肿瘤免疫相互作用组的技术 感受器。这个系统，我们称之为肿瘤免疫相互作用组无偏见发现报告(TIINDR)， 将允许我们询问转移肿瘤模型中的免疫相互作用因素和非相互作用因素，以便 了解转移性免疫监测的性质和后果。 总而言之，这项拟议的研究将为免疫监视和 确定新的和可操作的靶点，以改进治疗转移性疾病的免疫治疗策略。

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.