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

 描述(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完全相似的小鼠模型，特别是人类免疫环境。免疫系统以复杂和不完全了解的方式深刻地影响对肿瘤生长和转移的生理反应。众所周知，人类的免疫系统与老鼠的免疫系统有很大的不同。因此，非常需要更好的小鼠模型，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，这将使机制研究以及联合疗法的测试成为可能。为了解决这个问题，我们的团队建立了MISTRG，这是一种人源化的小鼠品系，移植了人类造血祖细胞(HPC)，表达了四种编码对先天性免疫细胞发育至关重要的细胞因子的基因的人类版本，最重要的是人类巨噬细胞(MF)。我们发现，在人源化的MISTRG小鼠中，人MF渗透到人类黑色素瘤细胞系衍生的肿瘤中的方式与从患者身上观察到的肿瘤相似。这与加速肿瘤进展有关，并涉及促血管生成因子血管内皮生长因子。这些有希望的初步发现表明，MISTRG是研究免疫介导的肿瘤发生机制的一个有价值的模型。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签名并在患者的肿瘤中证实这些签名，来证明人源化的MISTRG模型。目的1在供体CD34 HPC和黑色素瘤细胞系重组的MISTRG小鼠体内，确定人黑色素瘤肿瘤的构筑及其对人肿瘤浸润性免疫细胞的影响。目标2将定义人类黑色素瘤如何改变MISTRG小鼠的人类系统免疫。目的3将在自体系统中验证MISTRG模型，在该系统中，MISTRG小鼠与患者CD34 HPC和自体肿瘤重组。我们期望这一策略将产生候选的治疗靶点，以及一个忠实和强大的体内系统，用于旨在解开人类免疫系统和人类黑色素瘤之间关系的关键驱动因素的机械性研究。

 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.