Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma.
Synergistic effects of the immune checkpoint inhibitor CTLA-4 combined with the growth inhibitor lycorine in a mouse model of renal cell carcinoma.
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DOI：
10.18632/oncotarget.15505
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发表时间：
2017-03-28
期刊：
影响因子：
--
通讯作者：
Liu C
中科院分区：
文献类型：
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作者：
Li X;Xu P;Wang C;Xu N;Xu A;Xu Y;Sadahira T;Araki M;Wada K;Matsuura E;Watanabe M;Zheng J;Sun P;Huang P;Nasu Y;Liu C
肾细胞癌（RCC）的管理在过去十年中经历了重大转变;免疫检查点抑制剂目前正在进行临床试验，并显示出有希望的结果。然而，免疫检查点抑制剂在转移性RCC（mRCC）患者中的有效性仍然有限。石蒜碱是一种从石蒜科植物中提取的生物碱，由于其显著的生长抑制能力（诱导细胞周期停滞和抑制血管生成拟态形成）而被吹捧为潜在的抗癌药物。此外，使用靶向细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的抗体的T细胞检查点阻断疗法改善了癌症患者的结果。然而，石蒜碱和抗CTLA-4联合治疗的抗肿瘤功效仍然未知。因此，我们使用鼠RCC模型研究了盐酸石蒜碱和抗CTLA-4的联合治疗。作为体外确认的手段，我们发现盐酸石蒜碱抑制各种RCC细胞系的活力。此外，将表达肾癌酶的Renca细胞植入BALB/c小鼠的左肾和肺中以开发RCC转移性小鼠模型。盐酸石蒜碱和抗CTLA-4协同降低肿瘤重量、肺转移和肿瘤图像中的白蛋白染色。重要的是，观察到的该组合的抗肿瘤作用依赖于显著抑制调节性T细胞，同时上调效应T细胞;与对照组相比，在组合组中观察到调节性T细胞减少31.43%，但效应T细胞增加31.59%。我们认为盐酸石蒜碱和抗CTLA-4的组合是RCC患者的可行治疗选择。
Renal cell carcinoma (RCC) management has undergone a major transformation over the past decade; immune checkpoint inhibitors are currently undergoing clinical trials and show promising results. However, the effectiveness of immune checkpoint inhibitors in patients with metastatic RCC (mRCC) is still limited. Lycorine, an alkaloid extracted from plants of the Amaryllidaceae family, is touted as a potential anti-cancer drug because of its demonstrative growth inhibition capacity (induction of cell cycle arrest and inhibition of vasculogenic mimicry formation). Moreover, T cell checkpoint blockade therapy with antibodies targeting cytotoxic T-lymphocyte associated protein 4 (CTLA-4) has improved outcomes in cancer patients. However, the anti-tumor efficacy of combined lycorine and anti-CTLA-4 therapy remains unknown. Thus, we investigated a combination therapy of lycorine hydrochloride and anti-CTLA-4 using a murine RCC model. As a means of in vitro confirmation, we found that lycorine hydrochloride inhibited the viability of various RCC cell lines. Furthermore, luciferase-expressing Renca cells were implanted in the left kidney and the lung of BALB/c mice to develop a RCC metastatic mouse model. Lycorine hydrochloride and anti-CTLA-4 synergistically decreased tumor weight, lung metastasis, and luciferin-staining in tumor images. Importantly, the observed anti-tumor effects of this combination were dependent on significantly suppressing regulatory T cells while upregulating effector T cells; a decrease in regulatory T cells by 31.43% but an increase in effector T cells by 31.59% were observed in the combination group compared with those in the control group). We suggest that a combination of lycorine hydrochloride and anti-CTLA-4 is a viable therapeutic option for RCC patients.