Division of Hematology-Oncology, Department of Internal Medicine, Chonnam National University Medical School and Hwasun Hospital, 322 Seoyang-Ro, Hwasun-Eup, Hwasun-Gun, Jeollanam-Do, 58128, Republic of Korea.
Department of Pathology, Bio-Medical Sciences Graduate Program (BMSGP), Chonnam National University Research Institute of Medical Science, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Republic of Korea.
Sci Rep. 2024 Sep 2;14(1):20338. doi: 10.1038/s41598-024-69988-y.
Preclinical drug efficacy and tumor microenvironment (TME) investigations often utilize humanized xenograft mouse models, yet these models typically fall short in replicating the intricate TME. We developed a humanized liver metastasis (LM) model by transplanting human peripheral blood mononuclear cells (PBMCs) and assessed it against the conventional subcutaneous (SC) xenograft model, focusing on immune cell dynamics post-transplantation and immunotherapy response. NOD-scid IL2Rgamma(NSG) were inoculated with PBMCs to create humanized models. We induced SC and LM models using HCT116 cells, to investigate and compare the distributions and transformations of immune cell subsets, respectively. Both models were subjected to anti-PD-L1 therapy, followed by an analysis the TME analysis. The LM model demonstrated enhanced central tumor infiltration by tumor-infiltrating lymphocytes (TILs) compared to the peripheral pattern of SC model. TIL subpopulations in the LM model showed a progressive increase, contrasting with an initial rise and subsequent decline in the SC model. Post-anti-PD-L1 therapy, the LM model exhibited a significant rise in central and effector memory T cells, a response absents in the SC model. Our study highlights differential TME responses between SC and LM models and introduces a robust humanized LM model that swiftly indicates the potential efficacy of immunotherapies. These insights could streamline the preclinical evaluation of TME-targeting immunotherapeutic agents.
临床前药物疗效和肿瘤微环境（TME）研究常采用人源化异种移植小鼠模型，但这些模型通常无法复制复杂的 TME。我们通过移植人外周血单核细胞（PBMC）开发了一种人源化肝转移（LM）模型，并将其与传统的皮下（SC）异种移植模型进行了评估，重点关注移植后免疫细胞动力学和免疫治疗反应。通过向 NOD-scid IL2Rgamma（NSG）接种 PBMC 来建立人源化模型。我们使用 HCT116 细胞诱导 SC 和 LM 模型，分别研究和比较免疫细胞亚群的分布和转化。对两种模型均进行抗 PD-L1 治疗，然后进行 TME 分析。与 SC 模型的外周模式相比，LM 模型显示中央肿瘤浸润的肿瘤浸润淋巴细胞（TIL）增强。LM 模型中的 TIL 亚群呈逐渐增加趋势，而 SC 模型则呈初始增加后随后下降的趋势。抗 PD-L1 治疗后，LM 模型中中央和效应记忆 T 细胞显著增加，而 SC 模型则没有这种反应。我们的研究强调了 SC 和 LM 模型之间 TME 反应的差异，并介绍了一种稳健的人源化 LM 模型，该模型能够迅速指示免疫疗法的潜在疗效。这些见解可以简化针对 TME 的免疫治疗药物的临床前评估。
