利用稳态外周血造血干细胞和祖细胞建立人源化小鼠模型,有助于筛选癌症靶向 T 细胞基因组

Cancer Innovation Pub Date : 2024-04-15 DOI:10.1002/cai2.118
Yulin Xu, Wei Shan, Qian Luo, Meng Zhang, Dawei Huo, Yijin Chen, Honghu Li, Yishan Ye, Xiaohong Yu, Yi Luo, He Huang
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引用次数: 0

摘要

背景 癌症靶向 T 细胞受体 T(TCR-T)细胞有望治疗血液恶性肿瘤和乳腺癌等癌症。然而,获得癌症反应性 TCR-T 细胞的方法一直不成功。 方法 在这里,我们开发了一种新策略,利用具有特异性免疫指纹的特殊人源化小鼠模型筛选癌症靶向 TCR-T 细胞。通过对稳态外周血单核细胞进行三维培养,扩增稀有的稳态循环造血干细胞和祖细胞,然后将扩增的细胞用于建立人源化小鼠。根据树突状细胞、单核细胞、T 细胞亚群和细胞因子的动力学,对人的免疫系统进行了评估。为了充分刺激免疫反应并获得 B 细胞前体 NAML-6 和三阴性乳腺癌 MDA-MB-231 靶向 TCR-T 细胞,我们使用上述灭活细胞处理人源化小鼠,每天两次,每次 7 天。然后,处理人T细胞,进行TCR β-链(TRB)测序分析。在构建了TCR β-链(TRB)序列后,研究了TCR β-链的比例、多样性和免疫特征等特征。 结果 结果表明,治疗后 T 细胞的多样性和克隆性都有所增加。TRBV、TRBJ和V-J组合的优先使用情况和特征也发生了变化。应激还诱导了高度的克隆扩增。肿瘤负荷和存活率分析表明,应激诱导能显著抑制随后输注的活肿瘤细胞的生长,延长人源化小鼠的存活时间。 结论 我们构建了一个个性化人源化小鼠模型来筛选癌症靶向 TCR-T 池。我们的平台提供了癌症靶向 TCR-T 细胞的有效来源,并允许设计患者特异性工程 T 细胞。因此,它有可能极大地促进癌症治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires

Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires

Background

Cancer-targeted T-cell receptor T (TCR-T) cells hold promise in treating cancers such as hematological malignancies and breast cancers. However, approaches to obtain cancer-reactive TCR-T cells have been unsuccessful.

Methods

Here, we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune fingerprints. Rare steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells, and then the expanded cells were applied to establish humanized mice. The human immune system was evaluated according to the kinetics of dendritic cells, monocytes, T-cell subsets, and cytokines. To fully stimulate the immune response and to obtain B-cell precursor NAML-6- and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells, we used the inactivated cells above to treat humanized mice twice a day every 7 days. Then, human T cells were processed for TCR β-chain (TRB) sequencing analysis. After the repertoires had been constructed, features such as the fraction, diversity, and immune signature were investigated.

Results

The results demonstrated an increase in diversity and clonality of T cells after treatment. The preferential usage and features of TRBV, TRBJ, and the V–J combination were also changed. The stress also induced highly clonal expansion. Tumor burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized mice.

Conclusions

We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T pools. Our platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells. It therefore has the potential to greatly benefit cancer treatment.

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