Humanized mouse models to dissect in vivo the interplay between melanoma and the immune system

 描述（由申请人提供）：黑色素瘤是一种复杂而致命的疾病，需要新的治疗方法。然而，研究和治疗突破的一个主要障碍是缺乏与人类疾病，特别是人类免疫环境相似的小鼠模型。免疫系统以复杂且不完全理解的方式深刻地影响对肿瘤生长和转移的生理反应。还已知人的免疫系统与小鼠的免疫系统显著不同。因此，非常需要更好的小鼠模型，其能够在体内研究人类癌症和人类免疫系统之间的相互作用，这将能够进行机制研究以及测试组合疗法。为了克服这一问题，我们的小组建立了MISTRG，这是一种移植了人类造血祖细胞（HPC）的人源化小鼠品系，并表达编码对先天免疫细胞发育重要的细胞因子（最重要的是人类巨噬细胞（MF））的四种基因的人类版本。我们表明，人MF浸润人源化MISTRG小鼠中的人黑素瘤细胞系来源的肿瘤，其方式类似于在从患者获得的肿瘤中观察到的方式。这与加速肿瘤进展有关，并涉及促血管生成因子VEGF。这些有希望的初步研究结果表明，MISTRG是一个有价值的模型，研究免疫介导的肿瘤发生机制。在这里，我们建议扩展这些概念验证实验，并通过建立与黑色素瘤进展相关的转录特征并在患者肿瘤中确认这些特征来证明人源化MISTRG模型。目的1将确定人黑色素瘤肿瘤的结构及其对用供体CD34+ HPC和黑色素瘤细胞系重建的MISTRG小鼠体内人肿瘤浸润免疫细胞的影响。目的2将定义人黑色素瘤如何改变MISTRG小鼠中的人全身免疫。目的3将在自体系统中验证MISTRG模型，其中MISTRG小鼠用患者CD34+ HPC和自体肿瘤重建。我们期望这种策略产生候选治疗靶点以及用于机制研究的忠实和稳健的体内系统，旨在揭示人类免疫系统与人类黑色素瘤之间关系的关键驱动因素。

 DESCRIPTION (provided by applicant): Melanoma is a complex and deadly disease for which new therapies are needed. A major barrier to research and therapeutic breakthroughs, however, is the lack of mouse models properly resembling the human disease, and in particular, the human immune environment. The immune system profoundly affects physiological responses to tumor growth and metastasis in ways that are complex and incompletely understood. It is also known that the human immune system differs significantly from that of a mouse. Thus, there is a great need for better mouse models that enable in vivo studies of the interplay between human cancer and the human immune system, which would enable both mechanistic studies as well as the testing of combination therapies. To surmount this issue our group established MISTRG, a humanized mouse strain transplanted with human hematopoietic progenitor cells (HPCs) and expressing human versions of four genes encoding cytokines important for innate immune-cell development, most importantly human macrophages (MF). We showed that human MF infiltrated a human melanoma cell line-derived tumor in humanized MISTRG mice in a manner resembling that observed in tumors obtained from patients. This was associated with accelerated tumor progression and involved the pro-angiogenesis factor VEGF. These promising preliminary findings suggest that MISTRG is a valuable model for investigating the immune-mediated mechanisms of tumorigenesis. Here, we propose to extend these proof-of-concept experiments, and to credential the humanized MISTRG model, by establishing transcriptional signatures linked with melanoma progression and confirming these signatures in tumors from patients. Aim 1 will determine the architecture of human melanoma tumors and their impact on human tumor-infiltrating immune cells in vivo in MISTRG mice reconstituted with donor CD34+ HPCs and melanoma cell lines. Aim 2 will define how human melanoma alters the human systemic immunity in MISTRG mice. Aim 3 will validate the MISTRG model in an autologous system where MISTRG mice are reconstituted with patient CD34+ HPCs and autologous tumors. We expect this strategy to yield candidate therapeutic targets as well as a faithful and robust in vivo system for mechanistic studies aimed at unraveling key drivers of the relationship between the human immune system and human melanoma.