PDF(Pubmed)
Abstract：
BACKGROUND: Preclinical models are often used for cancer studies and evaluation of novel therapeutics. The relevance of these models has vastly improved with mice bearing a human immune system, especially in the context of immunotherapy. Nonetheless, cancer is an age-related disease, and studies often overlook the effects of aging. Here we have established a humanized mouse model of human immune aging to investigate the role of this phenomenon on liver tumor dynamics.
METHODS: Multiple organs and tissues (blood, thymus, lung, liver, spleen and bone marrow) were harvested from NOD-scid IL2rγ-/- (NIKO) mice reconstituted with human immune cells, over a period of 60 weeks post-birth, for immune profiling. Young and aging immune cells were compared for transcriptomic changes and functional differences. Effect of immune aging was investigated in a liver cancer humanized mouse model.
RESULTS: Focusing on the T cell population, which is central to cancer immunosurveillance and immunotherapy, we showed that the proportion of naïve T cells declined while memory subsets and senescent-like cells increased with age. RNA-sequencing revealed that downregulated genes were related to immune responses and processes, and this was corroborated by reduced cytokine production in aging T cells. Finally, we showed faster liver tumor growth in aging than younger humanized mice, which could be attributed to specific pathways of aging T cell exhaustion.
CONCLUSIONS: Our work improves on existing humanized (immune) mouse model and highlights the importance of considering immune aging in liver cancer modeling.
METHODS: Multiple organs and tissues (blood, thymus, lung, liver, spleen and bone marrow) were harvested from NOD-scid IL2rγ-/- (NIKO) mice reconstituted with human immune cells, over a period of 60 weeks post-birth, for immune profiling. Young and aging immune cells were compared for transcriptomic changes and functional differences. Effect of immune aging was investigated in a liver cancer humanized mouse model.
RESULTS: Focusing on the T cell population, which is central to cancer immunosurveillance and immunotherapy, we showed that the proportion of naïve T cells declined while memory subsets and senescent-like cells increased with age. RNA-sequencing revealed that downregulated genes were related to immune responses and processes, and this was corroborated by reduced cytokine production in aging T cells. Finally, we showed faster liver tumor growth in aging than younger humanized mice, which could be attributed to specific pathways of aging T cell exhaustion.
CONCLUSIONS: Our work improves on existing humanized (immune) mouse model and highlights the importance of considering immune aging in liver cancer modeling.
摘要：
背景技术临床前模型通常用于癌症研究和新疗法的评估。这些模型的相关性在携带人类免疫系统的小鼠中得到了极大的改善，特别是在免疫治疗方面。尽管如此，癌症是一种与年龄有关的疾病，而研究往往忽视了衰老的影响。在这里，我们建立了人类免疫衰老的人源化小鼠模型，以研究这种现象对肝脏肿瘤动力学的作用。
方法：多个器官和组织（血液，胸腺,肺，肝脏,脾和骨髓）从用人免疫细胞重建的NOD-scidIL2rγ-/-（NIKO）小鼠中收获，在出生后的60周内，用于免疫分析。比较了年轻和衰老的免疫细胞的转录变化和功能差异。在肝癌人源化小鼠模型中研究了免疫衰老的影响。
结果：关注T细胞群，这是癌症免疫监视和免疫疗法的核心，我们发现，初始T细胞的比例随着年龄的增长而下降，而记忆亚群和衰老样细胞的比例增加。RNA测序显示下调的基因与免疫反应和过程有关，衰老T细胞中细胞因子的产生减少证实了这一点。最后,我们在衰老过程中显示出比年轻的人源化小鼠更快的肝脏肿瘤生长，这可能归因于衰老T细胞衰竭的特定途径。
结论：我们的工作改进了现有的人源化（免疫）小鼠模型，并强调了在肝癌建模中考虑免疫老化的重要性。
方法：多个器官和组织（血液，胸腺,肺，肝脏,脾和骨髓）从用人免疫细胞重建的NOD-scidIL2rγ-/-（NIKO）小鼠中收获，在出生后的60周内，用于免疫分析。比较了年轻和衰老的免疫细胞的转录变化和功能差异。在肝癌人源化小鼠模型中研究了免疫衰老的影响。
结果：关注T细胞群，这是癌症免疫监视和免疫疗法的核心，我们发现，初始T细胞的比例随着年龄的增长而下降，而记忆亚群和衰老样细胞的比例增加。RNA测序显示下调的基因与免疫反应和过程有关，衰老T细胞中细胞因子的产生减少证实了这一点。最后,我们在衰老过程中显示出比年轻的人源化小鼠更快的肝脏肿瘤生长，这可能归因于衰老T细胞衰竭的特定途径。
结论：我们的工作改进了现有的人源化（免疫）小鼠模型，并强调了在肝癌建模中考虑免疫老化的重要性。
