Centre de Recherche du CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, QC H3T 1C5, Canada.
Département de Pharmacologie et Physiologie, Montréal, QC, Canada.
Cell Rep Methods. 2022 Jan 14;2(1):100153. doi: 10.1016/j.crmeth.2021.100153. eCollection 2022 Jan 24.
Modeling the tumor-immune cell interactions in humanized mice is complex and limits drug development. Here, we generated easily accessible tumor models by transforming either primary skin fibroblasts or induced pluripotent stem cell-derived cell lines injected in immune-deficient mice reconstituted with human autologous immune cells. Our results showed that fibroblastic, hepatic, or neural tumors were all efficiently infiltrated and partially or totally rejected by autologous immune cells in humanized mice. Characterization of tumor-immune infiltrates revealed high expression levels of the dysfunction markers Tim3 and PD-1 in T cells and an enrichment in regulatory T cells, suggesting rapid establishment of immunomodulatory phenotypes. Inhibition of PD-1 by Nivolumab in humanized mice resulted in increased immune cell infiltration and a slight decrease in tumor growth. We expect that these versatile and accessible cancer models will facilitate preclinical studies and the evaluation of autologous cancer immunotherapies across a range of different tumor cell types.
在人源化小鼠中模拟肿瘤-免疫细胞相互作用比较复杂，限制了药物的开发。在这里，我们通过将原代皮肤成纤维细胞或诱导多能干细胞衍生的细胞系注射到用人自体免疫细胞重建的免疫缺陷小鼠中，生成了易于获取的肿瘤模型。我们的结果表明，成纤维细胞瘤、肝癌或神经细胞瘤在人源化小鼠中均被自体免疫细胞有效浸润，并被部分或完全排斥。对肿瘤-免疫浸润物的特征分析显示，T 细胞中 Tim3 和 PD-1 等功能障碍标志物的表达水平较高，调节性 T 细胞富集，表明免疫调节表型的快速建立。在人源化小鼠中用 Nivolumab 抑制 PD-1 可增加免疫细胞浸润，并使肿瘤生长略有下降。我们预计这些多功能且易于获取的癌症模型将促进临床前研究和对一系列不同肿瘤细胞类型的自体癌症免疫疗法的评估。
