Evaluation of the immunomodulatory activity of thalidomide on tumor-associated macrophages in the 4T1 murine metastatic breast cancer model

ABSTRACT The present work evaluated the immunomodulatory effect of thalidomide (Thal) at different doses on tumor-associated macrophages (TAMs) using a mouse model of human breast cancer. Mice were inoculated with 4T1 cells in the left flank and treated with Thal once a day at concentrations of 50, 100, and 150mg/kg body weight from the 5th day until the 28th day of tumor inoculation. The tumors were sized, proliferation index and TAMs count were evaluated in primary tumors and metastatic lungs. In addition, the metastasis rate was evaluated in the lungs. Thal at 150mg/kg significantly decreased tumor growth, proliferation index, and TAMs infiltration in primary tumors. Conversely, a higher number of TAMs and lower proliferation index were observed in metastatic lungs in mice treated with 150mg/kg of Thal. Furthermore, Thal at 150mg/kg significantly decreased the metastatic nodules in the lungs. Our findings demonstrated that Thal treatment considerably decreased the primary tumor and lung metastasis in mice associated with different TAM infiltration effects in these sites.

摘要 本研究采用人乳腺癌小鼠模型，评估了不同剂量沙利度胺（thalidomide，Thal）对肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）的免疫调节作用。小鼠左侧侧腹皮下接种4T1细胞，自肿瘤接种后第5日至第28日，分别以50、100、150mg/kg体重的剂量每日给药一次。本研究对肿瘤体积进行测量，并检测了原发肿瘤及转移性肺组织的增殖指数与肿瘤相关巨噬细胞计数；此外还评估了肺部转移发生率。结果显示，150mg/kg剂量的沙利度胺可显著抑制原发肿瘤生长，降低增殖指数，并减少原发肿瘤内的肿瘤相关巨噬细胞浸润。与之相反，接受150mg/kg沙利度胺治疗的小鼠，其转移性肺组织中肿瘤相关巨噬细胞数量更高，而增殖指数更低。进一步分析表明，150mg/kg剂量的沙利度胺可显著减少肺部转移结节数量。本研究结果证实，沙利度胺给药可显著降低小鼠原发肿瘤负荷与肺部转移程度，且该作用与不同部位的肿瘤相关巨噬细胞浸润水平变化密切相关。