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

人源化小鼠模型在体内剖析黑色素瘤与免疫系统之间的相互作用

• 批准号: 8902610
• 负责人: Richard A. Flavell
• 金额: $ 46.72万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-14 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8902610
• 关键词: Affect; Angiogenic Factor; Antibodies; Architecture; Autologous; Avastin; Blood; Bone Marrow; Breast Melanoma; CD34 gene; Cell Line; Cell Separation; Cells; Combined Modality Therapy; Complex; Confocal Microscopy; Dendritic Cells; Development; Disease; Environment; Flow Cytometry; Genes; Hematopoietic stem cells; Human; Human Development; Immune; Immune response; Immune system; Immunity; Implant; In Situ Hybridization; Infiltration; Kinetics; Link; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Mediating; Melanoma Cell; Modeling; Molecular Profiling; Mouse Strains; Mus; Myeloid Cells; Natural Immunity; Neoplasm Metastasis; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Physiological; Population; Research; Role; Sampling; Study models; Surface; System; Testing; Therapeutic Human Experimentation; Time; Transplantation; Tumor-Derived; Vascular Endothelial Growth Factors; Whole Blood; cancer immunotherapy; cytokine; human cancer mouse model; human disease; in vivo; inhibitor/antagonist; laser capture microdissection; macrophage; malignant breast neoplasm; melanoma; monocyte; mouse model; neoplastic cell; novel; public health relevance; reconstitution; research study; response; therapeutic target; transcriptome sequencing; tumor; tumor growth; tumor progression; tumorigenesis

 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.

 描述（由申请人提供）：黑色素瘤是一种复杂且致命的疾病，需要新的疗法，然而，研究和治疗突破的一个主要障碍是缺乏与人类疾病、特别是人类疾病完全相似的小鼠模型。免疫系统以复杂且不完全了解的方式深刻影响着肿瘤生长和转移的生理反应，因此，非常需要更好的免疫系统。老鼠能够对人类癌症与人类免疫系统之间相互作用进行体内研究的模型，这将能够进行机制研究以及联合疗法的测试。为了克服这个问题，我们的团队建立了 MSTRG，一种移植了人类造血系统的人源化小鼠品系。祖细胞（HPC）并表达编码对先天免疫细胞发育很重要的细胞因子的人类版本，最重要的是人类巨噬细胞（MF）。我们发现人类 MF 浸润了人类黑色素瘤细胞。在人源化 MSTRG 小鼠中观察到的细胞系衍生肿瘤的方式与在从患者获得的肿瘤中观察到的方式相似，这与加速肿瘤进展有关，并涉及促血管生成因子 VEGF。这些有希望的初步发现表明，MSTRG 是研究该疾病的一个有价值的模型。在这里，我们建议通过建立与黑色素瘤进展相关的转录特征并在肿瘤中确认这些特征来扩展这些概念验证实验，并验证人源化 MISTRG 模型。目标 1 将确定人类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组的 MSTRG 小鼠体内人类肿瘤浸润免疫细胞的影响；目标 2 将确定人类黑色素瘤如何改变人类全身免疫。目标 3 将在自体系统中验证 MSTRG 模型，其中 MSTRG 小鼠用患者 CD34+ HPC 重建，并且我们期望这一策略能够产生候选治疗靶点以及可靠且强大的体内系统，用于机制研究，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。