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PHE- 对术语的理解还不完全。巨噬细胞是一种多功能免疫细胞，存在于所有组织中。 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、转移扩散和患者生存期缩短相关，但TME Mac- 罗氏噬菌体还没有在成功的治疗中成为特定的靶点。这个项目的目的是为了-- 阐明巨噬细胞促进转移癌扩散的细胞和分子机制，以及 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”模型携带移植的人类免疫系统，包括功能性人Mac-- 其中共同移植的实体瘤生长和转移。利用这一实验系统 模型人类黑色素瘤，我们已经表明，人类巨噬细胞在促进META- 总结临床观察。通过单细胞RNA测序，我们已经识别出一种独特的、唯一的 TME定位的人巨噬细胞群体以及潜在分化的候选机制 以及这些细胞的存活。我们的中心假设是药物靶向这些TME巨噬细胞 可用于预防和/或控制癌症患者的转移扩散。在我们强大的初步指导下 数据，我们将使用最先进的技术和以下三个具体目标来验证我们的假设。我们会： (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的癌症类型，并从功能上测试这些宏模型在体内的作用 人源化小鼠患者来源的异种移植(“免疫PDX”)中的噬菌体； 这些巨噬细胞在TME中分化和存活；以及(3)决定TME的机制 巨噬细胞支持转移。拟议研究的预测结果是，我们将严格 人类肿瘤中支持转移的巨噬细胞的特征和新的候选靶点 癌症疗法。专门针对这些巨噬细胞，作为单一疗法或与其他 现有的治疗方法，可能会对目前治疗无效的患者产生积极影响。最后， 拟议实验中的积极发现将进一步推动我们的人源化小鼠模型作为一种高度 免疫肿瘤学翻译研究的宝贵研究工具，包括对新疗法的评估 相关的临床前情况。

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.