Applicability of Mouse Breast Cancer Models to Tumor-Immune Network Investigation

 描述（由申请人提供）：在过去的几十年里，小鼠癌症模型提供了关于致癌转化和肿瘤发展过程的许多必要的见解。然而，很少有研究调查调节癌症发展和扩散的核心肿瘤-免疫相互作用是否在小鼠中保守，但越来越多的证据支持免疫系统在影响肿瘤发生和进展的各个方面中发挥核心作用。不幸的是，免疫系统及其行为状态的复杂性已经超过了基于荧光的流式细胞术和常规免疫组织化学（IHC）的技术限制。质量细胞计数和多路离子束成像（MIBI）的发展使研究人员能够比以往任何时候都更彻底地检测整个免疫系统。通过将流式细胞术的通量与质谱的精确度相结合，质谱细胞术已经扩大了可以在单细胞上同时测量的参数的数量。同样，MIBI也极大地增加了可以在单个组织切片中对数十种蛋白质成像的参数数量。这些方法与新的分析算法相结合，使小鼠和人类之间的免疫组织的系统范围内的比较。我们将这些新的工具应用于乳腺癌的设置，具体目的是辨别小鼠模型和相同组织学来源的原发性患者样本之间的相似性和差异。我们的具体目标是：1）揭示免疫浸润的表型和功能的相似性 在人类和小鼠中转移性乳腺癌与非转移性乳腺癌中的作用; 2）通过从正常组织到早期瘤形成和转移性疾病的进展阐明人类和小鼠中免疫系统的组成和行为;和3）揭示标准护理疗法对小鼠和人类乳腺癌中免疫浸润的作用。这些研究将为临床前肿瘤免疫网络的研究提供指南 小鼠乳腺癌模型，以确定哪些发现可能适用于跨越物种障碍。此外，拟议的研究将为确定小鼠模型在任何癌症或任何治疗中的适用性奠定基础。

 DESCRIPTION (provided by applicant): Mouse models of cancer have provided much necessary insight regarding the processes of oncogenic transformation and tumor development over the last decades. However, few studies have investigated whether the core tumor-immune interactions that regulate cancer development and spread are conserved in mice, and yet accumulating evidence supports a central role for the immune system in impacting all facets of tumorigenesis and progression. Unfortunately, the complexity of the immune system and its behavioral states has surpassed the technical limitations of fluorescence-based flow cytometry and conventional immunohistochemistry (IHC). The development of mass cytometry and multiplexed ion beam imaging (MIBI) allows investigators to assay the immune system as a whole more thoroughly than ever before. Mass cytometry has expanded the number of parameters that can be simultaneously measured on single cells by combining the throughput of flow cytometry with the precision of mass spectrometry. Similarly, MIBI has dramatically increased the number of parameters that can be imaged to dozens of proteins in a single tissue section. The combination of these methods with new analytical algorithms enables a systems-wide comparison of immune organization between mice and humans. We will apply these novel tools to the setting of breast cancer with the specific intent of discerning similarities and differences between mouse models and primary patient samples of the same histological origin. Our specific aims are to 1) reveal similarities in the phenotype and function of immune infiltrates in metastatic versus non-metastatic breast cancer in humans and mice; 2) elucidate the composition and behavior of the immune system in humans and mice through progression from normal tissue through early neoplasia and metastatic disease; and 3) reveal the effect(s) of standard-of-care therapies on the immune infiltrate in mouse and human breast cancer. These studies will result in guidelines for the investigation of the tumor-immune network in pre-clinical mouse models of breast cancer to determine which findings are likely applicable across the species barrier. Moreover, the proposed studies will lay the foundation for determining the suitability of mouse models in any cancer or for any treatment.