Background: With the rising incidence of cancer, there is a growing need for improved preclinical models to test new therapies. While patient-derived xenografts (PDX) in immunodeficient mice are the gold standard, they are costly and result in a complete absence of a functional immune system, limiting their utility for studying tumor–immune interactions. This study characterizes a pharmacological partial immunosuppression protocol in immunocompetent mice as a promising alternative, evaluating its impact on the immune system and demonstrating its efficacy for growing human tumor xenografts. Methods: Mice received a regimen of cyclosporine (20 mg/kg, i.p., every 48 h for 12 days), cyclophosphamide (60 mg/kg, i.p., every 48 h for 8 days), and ketoconazole (10 mg/kg, p.o., for 12 days). The dynamics of CD3+, CD4+, CD8+, and CD19+lymphocyte subpopulations and the CD4/CD8 index were monitored via flow cytometry on days 1, 5, 8, 12, 16, and 21. The protocol’s utility was tested by orthotopic transplantation of human glioma and lung cancer cells, and subcutaneous transplantation of breast cancer cells (MCF7). Tumor engraftment and growth were assessed using in vivo microscopy, MRI, and histology. Results: The immunosuppressive protocol induced a significant but partial reduction in CD3+T-cells and CD19+B-cells by day 8 (p= 0.0277). A profound and progressive decrease in the CD4/CD8 index was observed, indicating a shift towards immunosuppression. Crucially, CD8+and CD4+T-cells populations recovered rapidly post-therapy, demonstrating that the protocol creates a temporary and modifiable immune window rather than inducing complete ablation. The protocol enabled successful engraftment and growth of all three tested tumors in a residual immune microenvironment, confirmed by in vivo imaging and histopathological analysis. Conclusions: This drug-induced partial immunosuppression protocol effectively creates a reproducible state of transient immunodeficiency in outbred mice, suitable for various human tumor xenograft models. It represents a cost-effective and flexible alternative to genetic models, with the distinct advantage of preserving a residual immune microenvironment, making it particularly valuable for preclinical studies that require a partially intact host immune system.
背景：随着癌症发病率不断上升，对改进临床前模型以测试新疗法的需求日益增长。虽然免疫缺陷小鼠中的人源肿瘤异种移植（PDX）模型是金标准，但其成本高昂且导致功能性免疫系统完全缺失，限制了其在研究肿瘤-免疫相互作用中的应用。本研究旨在评估一种在免疫健全小鼠中实施的药物性部分免疫抑制方案，分析其对免疫系统的影响，并验证其用于人类肿瘤异种移植的可行性。 方法：小鼠接受环孢素（20 mg/kg，腹腔注射，每48小时一次，持续12天）、环磷酰胺（60 mg/kg，腹腔注射，每48小时一次，持续8天）和酮康唑（10 mg/kg，口服，持续12天）联合给药方案。通过流式细胞术在第1、5、8、12、16和21天监测CD3⁺、CD4⁺、CD8⁺和CD19⁺淋巴细胞亚群动态变化及CD4/CD8指数。通过原位移植人胶质瘤和肺癌细胞、皮下移植乳腺癌细胞（MCF7）验证该方案的有效性。采用活体显微成像、磁共振成像和组织学方法评估肿瘤定植与生长情况。 结果：免疫抑制方案在第8天引起CD3⁺ T细胞和CD19⁺ B细胞显著但部分减少（p=0.0277）。CD4/CD8指数呈现深度渐进性下降，表明免疫抑制状态转变。关键的是，CD8⁺和CD4⁺ T细胞群在治疗后迅速恢复，证明该方案创造的是暂时性、可调节的免疫窗口，而非完全免疫清除。在残留免疫微环境中，所有三种测试肿瘤均成功实现定植与生长，活体成像和组织病理学分析证实了这一结果。 结论：该药物诱导的部分免疫抑制方案能在远交系小鼠中有效建立可重复的短暂免疫缺陷状态，适用于多种人类肿瘤异种移植模型。相较于遗传模型，该方案具有成本效益高、灵活性强的优势，其突出特点在于能保留部分宿主免疫微环境，对需要部分完整免疫系统的临床前研究具有重要价值。
Drug-Induced Partial Immunosuppression for Preclinical Human Tumor Xenograft Models
肿瘤(癌症)患者之家