Establishment of peripheral blood mononuclear cell-derived humanized lung cancer mouse models for studying efficacy of PD-L1/PD-1 targeted immunotherapy
Establishment of peripheral blood mononuclear cell-derived humanized lung cancer mouse models for studying efficacy of PD-L1/PD-1 targeted immunotherapy
复制标题
建立外周血单核细胞源性人源化肺癌小鼠模型用于研究PD-L1/PD-1靶向免疫治疗的疗效
DOI：
10.1080/19420862.2018.1518948
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发表时间：
2018-01-01
期刊：
影响因子：
5.3
通讯作者：
Li, Peng
中科院分区：
文献类型：
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作者：
Lin, Shouheng;Huang, Guohua;Li, Peng
用于评价免疫检查点抑制剂疗效的动物模型不足或不准确。因此，我们研究了两种用于此目的的异种移植模型，目的是优化它们。一种方法涉及使用外周血单核细胞和细胞系来源的异种移植物（PBMC-CDX模型）。对于这个模型，我们将人肺癌细胞植入NOD-scid-IL2Rg −/−（NSI）小鼠，然后注射人PBMC。第二种方法涉及使用造血干细胞和祖细胞以及CDX（HSPCs-CDX模型）。对于该模型，我们首先通过转移人CD34+造血干细胞和祖细胞（HSPC衍生的人源化模型）重建人免疫系统，然后移植人肺癌细胞。我们发现PBMCs-CDX模型在评估PD-L1/PD-1靶向免疫治疗方面更准确。此外，PBMCs-CDX模型仅需4周即可进行疗效评估，而HSPCs-CDX模型需要10 - 14周。然后，我们进一步建立了PBMC来源的患者来源的异种移植物（PDX）模型，包括使用来自相同肿瘤的癌症和T细胞的自体PBMC-PDX模型，并将其应用于评估抗PD-L1抗体的抗肿瘤功效。我们证明了这种PBMC衍生的PDX模型是研究PD-L1/PD-1靶向癌症免疫疗法疗效的宝贵工具。总的来说，我们发现我们的PBMC衍生模型是研究免疫检查点抑制剂的优秀临床前模型。
ABSTRACT Animal models used to evaluate efficacies of immune checkpoint inhibitors are insufficient or inaccurate. We thus examined two xenograft models used for this purpose, with the aim of optimizing them. One method involves the use of peripheral blood mononuclear cells and cell line-derived xenografts (PBMCs-CDX model). For this model, we implanted human lung cancer cells into NOD-scid-IL2Rg−/− (NSI) mice, followed by injection of human PBMCs. The second method involves the use of hematopoietic stem and progenitor cells and CDX (HSPCs-CDX model). For this model, we first reconstituted the human immune system by transferring human CD34+ hematopoietic stem and progenitor cells (HSPCs-derived humanized model) and then transplanted human lung cancer cells. We found that the PBMCs-CDX model was more accurate in evaluating PD-L1/PD-1 targeted immunotherapies. In addition, it took only four weeks with the PBMCs-CDX model for efficacy evaluation, compared to 10–14 weeks with the HSPCs-CDX model. We then further established PBMCs-derived patient-derived xenografts (PDX) models, including an auto-PBMCs-PDX model using cancer and T cells from the same tumor, and applied them to assess the antitumor efficacies of anti-PD-L1 antibodies. We demonstrated that this PBMCs-derived PDX model was an invaluable tool to study the efficacies of PD-L1/PD-1 targeted cancer immunotherapies. Overall, we found our PBMCs-derived models to be excellent preclinical models for studying immune checkpoint inhibitors.