Huang Xiao-Ming, Zhang Nan-Rong, Lin Xu-Tao, Zhu Cai-Yan, Zou Yi-Feng, Wu Xiao-Jian, He Xiao-Sheng, He Xiao-Wen, Wan Yun-Le, Lan Ping
Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Guangdong Institute of Gastroenterology; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.
Gastroenterol Rep (Oxf). 2019 Dec 5;8(1):56-65. doi: 10.1093/gastro/goz060. eCollection 2020 Feb.
The tumor immune microenvironment is one of the most important prognostic factors in liver metastasis from colorectal cancer. Low-dose cyclophosphamide (CTX) is widely believed to be involved in the modulation of the immune system. However, the underlying mechanism of low-dose CTX remains unknown. This study aimed to investigate the antitumor immunity of low-dose CTX in the treatment of colon-cancer liver metastasis.
Thirty mice were randomly divided into five groups. After liver metastasis was established in colon-cancer models, mice in the treatment groups were injected with low-dose CTX (20 mg/kg) at different time points. Liver and spleen tissues were examined for T-cell markers via flow cytometry. Interleukin (IL)-10 and transforming growth factor (TGF)-β1 expression levels in liver tissues were analysed by immunohistochemistry. Serum interferon (IFN)-γ and IL-10 levels were detected by enzyme-linked immunosorbent assay. An additional 20 mice were randomly allocated into two groups and the survival times were recorded.
The expression levels of CD4 T cells, CD8 T cells, and IFN-γ were down-regulated, whereas those of IL-10 and TGF-β1 were up-regulated in liver metastasis from colon cancer in mice. Furthermore, the local and systemic microenvironments of the liver were altered, which led to reduced antitumor immune responses and subsequently liver metastasis. However, treatment with low-dose CTX reversed these effects. The survival times of mice treated with low-dose CTX were significantly longer than those of the other groups.
Low-dose CTX exerts its antitumor activity by changing the systemic and local immune microenvironments and enhancing immune regulation in mice. CTX could be used as a drug to prevent and treat liver metastasis from colon cancer.
肿瘤免疫微环境是结直肠癌肝转移最重要的预后因素之一。低剂量环磷酰胺（CTX）被广泛认为参与免疫系统的调节。然而，低剂量CTX的潜在机制仍不清楚。本研究旨在探讨低剂量CTX在治疗结肠癌肝转移中的抗肿瘤免疫作用。
将30只小鼠随机分为五组。在结肠癌模型中建立肝转移后，治疗组小鼠在不同时间点注射低剂量CTX（20mg/kg）。通过流式细胞术检测肝脏和脾脏组织中的T细胞标志物。采用免疫组织化学分析肝脏组织中白细胞介素（IL）-10和转化生长因子（TGF）-β1的表达水平。采用酶联免疫吸附测定法检测血清干扰素（IFN）-γ和IL-10水平。另外20只小鼠随机分为两组，记录生存时间。
在小鼠结肠癌肝转移中，CD4 T细胞、CD8 T细胞和IFN-γ的表达水平下调，而IL-10和TGF-β1的表达水平上调。此外，肝脏的局部和全身微环境发生改变，导致抗肿瘤免疫反应降低，进而发生肝转移。然而，低剂量CTX治疗可逆转这些效应。低剂量CTX治疗的小鼠生存时间明显长于其他组。
低剂量CTX通过改变小鼠的全身和局部免疫微环境并增强免疫调节发挥其抗肿瘤活性。CTX可作为预防和治疗结肠癌肝转移的药物。
