临床前药物疗效和肿瘤微环境 (TME) 研究通常利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）开发了人源化肝转移（LM）模型，并根据传统皮下（SC）异种移植模型对其进行了评估，重点关注移植后的免疫细胞动力学和免疫治疗反应。用PBMC接种NOD-scid IL2Rgammanull(NSG)以创建人源化模型。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。两种模型均接受抗 PD-L1 治疗，然后进行 TME 分析。与 SC 模型的外周模式相比，LM 模型表现出肿瘤浸润淋巴细胞 (TIL) 增强的中央肿瘤浸润。 LM 模型中的 TIL 亚群呈现逐渐增加的趋势，与 SC 模型中最初的上升和随后的下降形成鲜明对比。抗 PD-L1 治疗后，LM 模型表现出中枢和效应记忆 T 细胞显着增加，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，并引入了一个强大的人源化 LM 模型，该模型可以迅速表明免疫疗法的潜在功效。这些见解可以简化 TME 靶向免疫治疗药物的临床前评估。© 2024。作者。

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 IL2Rgammanull(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.© 2024. The Author(s).