Tan Joel H L, Hwang You Yi, Chin Hui Xian, Liu Min, Tan Sue Yee, Chen Qingfeng
Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore, 138673, Republic of Singapore.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), 8A Biomedical Grove, Immunos Level 3 & 4, Singapore, 138648, Republic of Singapore.
Immun Ageing. 2023 Sep 27;20(1):49. doi: 10.1186/s12979-023-00374-4.
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.
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.
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.
Our work improves on existing humanized (immune) mouse model and highlights the importance of considering immune aging in liver cancer modeling.
临床前模型常用于癌症研究和新型治疗方法的评估。随着带有人类免疫系统的小鼠的出现，这些模型的相关性有了极大提高，尤其是在免疫治疗的背景下。尽管如此，癌症是一种与年龄相关的疾病，而研究往往忽视了衰老的影响。在此，我们建立了一种人类免疫衰老的人源化小鼠模型，以研究这种现象对肝肿瘤动态的作用。
从用人免疫细胞重建的NOD-scid IL2rγ（NIKO）小鼠出生后60周内采集多个器官和组织（血液、胸腺、肺、肝、脾和骨髓）进行免疫分析。比较年轻和衰老免疫细胞的转录组变化和功能差异。在肝癌人源化小鼠模型中研究免疫衰老的影响。
聚焦于对癌症免疫监视和免疫治疗至关重要的T细胞群体，我们发现随着年龄的增长，幼稚T细胞的比例下降，而记忆亚群和衰老样细胞增加。RNA测序显示下调的基因与免疫反应和过程相关，衰老T细胞中细胞因子产生减少证实了这一点。最后，我们发现衰老的人源化小鼠的肝肿瘤生长比年轻小鼠更快，这可能归因于衰老T细胞耗竭的特定途径。
我们的工作改进了现有的（免疫）人源化小鼠模型，并强调了在肝癌建模中考虑免疫衰老的重要性。
