淫羊藿次苷Ⅱ通过下调MDSC比例抑制小鼠肺癌生长的研究

Icariside Ⅱ Inhibits Lung Cancer Growth By Decreasing MDSC Ratio in Mice

目的观察淫羊藿次苷Ⅱ(Icariside Ⅱ, ICA Ⅱ)是否通过下调髓系来源抑制性细胞(myeloid-derived suppressor cells, MDSCs)比例负向调控肺癌的发生发展。方法 C57BL/6小鼠皮下注射Lewis肺癌细胞构建皮下肿瘤模型,予以等体积0.5%羧甲基纤维素钠溶液和ICA Ⅱ低、高剂量灌胃处理,观察皮下肿瘤生长情况,流式细胞术检测荷瘤小鼠外周血、脾脏和肿瘤组织内MDSCs和肿瘤组织内T淋巴细胞比例;酶联免疫法检测外周血清中IL-6和TNF-α水平;免疫组化法检测肿瘤组织中CD31和VEGFA表达情况。结果 ICA Ⅱ干预组瘤体明显缩小、瘤重较轻、脾脏变小(P<0.05或P<0.01);IL-6水平降低、TNF-α水平升高,且低剂量组效果较为显著(P<0.05或P<0.01);CD31和VEGFA表达下降(P<0.01);ICA Ⅱ并可显著下调小鼠外周血、脾脏和肿瘤组织内MDSCs的比例(P<0.01),促进T淋巴细胞浸润、升高CD_(4)^(+)/CD_(8)^(+)比例,高剂量组效果较为显著(均P<0.01)。结论 ICA II可通过下调MDSCs比例、减弱其免疫抑制活性,改善机体炎性微环境,阻碍血管生长,从而发挥显著抗肺癌作用。

Objective The aim of this study was to explore whether Icariside Ⅱ(ICAⅡ) plays anti-cancer effects by decreasing myeloid-derived suppressor cells(MDSCs) ratio in mice. Methods Lewis lung cancer cells(LLC) were subcutaneously injected into the C57 BL/6 mice to construct subcutaneous models. Mice were divided into three groups which were respectively treated with 0.5% sodium carboxymethyl cellulose and low and high dose of ICA Ⅱ(control group, low group and high group). The growth of subcutaneous tumors was observed, and the proportion of MDSCs and T lymphocytes in the peripheral blood, spleen and tumor tissues of tumor-bearing mice was measured by flow cytometry. The levels of IL-6 and TNF-α in peripheral blood were detected by ELISA. Immunohistochemistry was used to detect the expressions of CD31 and VEGFA in tumor tissues. Results The results demonstrated that compared with those of the control group, the volume and weight of subcutaneous tumor and spleen weight were markedly decreased in ICAⅡ low and high dose groups(P<0.05 or P<0.01). ICA Ⅱ obviously inhibited IL-6 while promoted TNF-α secretion(P<0.05 or P<0.01), and inhibited expressions of CD31 and VEGFA(P<0.01). More importantly, ICAⅡ, especially high dose, also significantly decreased the proportion of MDSCs in peripheral blood, spleen and tumor tissues(P<0.01) and promote the infiltration of T lymphocytes with increasing the ratio of CD_(4)^(+)/CD_(8)^(+)(P<0.01). Conclusion We could draw the conclusion that ICAⅡ can reduce the immunosuppressive activity of MDSCs by reducing the proportion of MDSCs, improve the inflammatory microenvironment and hinder angiogenesis, and thus playing a significant role in anti-lung cancer.