Targeting macrophages in metastatic cancer

摘要 转移是癌症相关死亡的主要原因，但这种复杂的转移的机制， 名词不完全理解。巨噬细胞是在所有组织中发现的多功能免疫细胞， 包括肿瘤微环境（TME）。三十多年来，人们已经知道，高密度的TME 巨噬细胞与癌症进展、转移扩散和较短的患者生存期相关，但TME mac- 在成功的治疗中，罗丹明还没有被特异性地靶向。本项目的目标是： 抑制巨噬细胞促进转移性癌症扩散的细胞和分子机制， 从而为开发有效的治疗方法提供科学依据。我们的工作依赖于一种创新的 “人源化小鼠”模型，其携带移植的人免疫系统，包括功能性人MAC， 并且其中共植入的实体瘤生长和转移。利用这个实验系统， 模型人黑色素瘤，我们已经表明，人巨噬细胞在促进转移中发挥重要作用， tasis，概括临床观察结果。通过单细胞RNA测序，我们已经确定了一个独特的， TME定位的人巨噬细胞群体，以及分化的候选机制 这些细胞的存活。我们的中心假设是，靶向这些TME巨噬细胞 可用于预防和/或控制癌症患者的转移性扩散。在我们强大的初步指导下， 数据，我们将测试我们的假设，使用最先进的技术和以下三个具体目标。我们将： (1)确定活检样本中是否存在相同的支持转移的TME巨噬细胞 代表个体患者和不同癌症类型，并在功能上测试这些宏- 免疫-PDX”）;（2）定义免疫-PDX的机制， 这些巨噬细胞在TME中分化和存活;（3）确定TME 巨噬细胞支持转移。拟议研究的预测结果是，我们将严格 表征人类癌症中支持转移的巨噬细胞，并提出新的候选靶点 癌症治疗特异性靶向这些巨噬细胞，作为单一疗法或与其他药物组合， 现有的治疗方法，可能会对目前治疗无效的患者产生积极的影响。最后， 在拟议的实验中的积极发现将进一步推进我们的人源化小鼠模型作为一个高度 免疫肿瘤学转化研究的宝贵研究工具，包括评估 相关临床前疾病。

Abstract Metastasis is the main cause of cancer-associated deaths, but the mechanisms underlying this complex phe- nomenon are incompletely understood. Macrophages are multifunctional immune cells found in all tissues, in- cluding in tumor microenvironments (TME). It has been known for over three decades that high densities of TME macrophages correlate with cancer progression, metastatic spread and shorter patient survival, but TME mac- rophages have not yet been specifically targeted in a successful therapy. The objective of this project is to elu- cidate the cellular and molecular mechanisms by which macrophages promote metastatic cancer spread, and thereby provide the scientific basis for the development of effective therapies. Our work relies on an innovative “humanized mouse” model that carries a transplanted human immune system, including functional human mac- rophages, and in which co-implanted solid tumors grow and metastasize. Using this experimental system to model human melanoma, we have shown that human macrophages play an essential role in promoting metas- tasis, recapitulating clinical observations. By single cell RNA sequencing, we have identified a unique, exclusively TME-localized human macrophage population, as well as candidate mechanisms underlying the differentiation and survival of these cells. Our central hypothesis is that pharmacologically targeting these TME macrophages could be used to prevent and/or manage metastatic spread in cancer patients. Guided by our strong preliminary data, we will test our hypothesis, using state-of-the-art technologies and following three specific aims. We will: (1) determine whether the same metastasis-supporting TME macrophages are present across biopsy samples representing individual patients and different cancer types, and functionally test the in vivo role of these macro- phages in humanized mouse patient-derived xenografts (“immuno-PDX”); (2) define the mechanisms by which these macrophages differentiate and survive in the TME; and (3) determine the mechanisms by which TME macrophages support metastasis. The predicted outcome of the proposed research is that we will rigorously characterize metastasis-supporting macrophages in human cancer, and advance candidate targets for novel cancer therapies. Specifically targeting these macrophages, as a monotherapy or in combination with other available therapies, could have a positive impact on patients for whom current treatments are ineffective. Finally, positive findings in the proposed experiments would further advance our humanized mouse model as a highly valuable research tool for translational research in immuno-oncology, including evaluations of novel therapies in relevant pre-clinical conditions.