Lin Tien-Jen, Liang Wen-Miin, Hsiao Pei-Wen, M S Pradeep, Wei Wen-Chi, Lin Hsin-Ting, Yin Shu-Yi, Yang Ning-Sun
Graduate Institute of Injury Prevention and Control, Taipei Medical University, Taipei, Taiwan, ROC; Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan, ROC; Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan, ROC; Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan, ROC; Taiwan International Graduate Program (TIGP), Molecular and Biological Agricultural Sciences Program, Academia Sinica, Taipei, Taiwan, ROC.
Biostatistics Center, China Medical University, Taichung, Taiwan, ROC; Institute of Environmental Health, Department of Public Health, School of Public Health, China Medical University, Taichung, Taiwan, ROC.
PLoS One. 2015 Oct 1;10(10):e0138335. doi: 10.1371/journal.pone.0138335. eCollection 2015.
Suppression of tumor metastasis is a key strategy for successful cancer interventions. Previous studies indicated that rapamycin (sirolimus) may promote tumor regression activity or enhance immune response against tumor targets. However, rapamycin also exhibits immunosuppressant effects and is hence used clinically as an organ transplantation drug. We hypothesized that the immunosuppressive activities of rapamycin might also negatively mediate host immunity, resulting in promotion of tumor metastasis. In this study, the effects of rapamycin and phytochemical shikonin were investigated in vitro and in vivo in a 4T1 mouse mammary tumor model through quantitative assessment of immunogenic cell death (ICD), autophagy, tumor growth and metastasis. Tumor-bearing mice were immunized with test vaccines to monitor their effect on tumor metastasis. We found that intraperitoneal (ip) administration of rapamycin after a tumor-resection surgery drastically increased the metastatic activity of 4T1 tumors. Possible correlation of this finding to human cancers was suggested by epidemiological analysis of data from Taiwan's National Health Insurance Research Database (NHIRD). Since our previous studies showed that modified tumor cell lysate (TCL)-pulsed, dendritic cell (DC)-based cancer vaccines can effectively suppress metastasis in mouse tumor models, we assessed whether such vaccines may help offset this rapamycin-promoted metastasis. We observed that shikonin efficiently induced ICD of 4T1 cells in culture, and DC vaccines pulsed with shikonin-treated TCL (SK-TCL-DC) significantly suppressed rapamycin-enhanced metastasis and Treg cell expansion in test mice. In conclusion, rapamycin treatment in mice (and perhaps in humans) promotes metastasis and the effect may be offset by treatment with a DC-based cancer vaccine.
抑制肿瘤转移是成功进行癌症干预的关键策略。先前的研究表明，雷帕霉素（西罗莫司）可能促进肿瘤消退活性或增强针对肿瘤靶点的免疫反应。然而，雷帕霉素也具有免疫抑制作用，因此在临床上用作器官移植药物。我们推测雷帕霉素的免疫抑制活性也可能对宿主免疫产生负面影响，从而促进肿瘤转移。在本研究中，通过对免疫原性细胞死亡（ICD）、自噬、肿瘤生长和转移进行定量评估，在体外和体内4T1小鼠乳腺肿瘤模型中研究了雷帕霉素和植物化学物质紫草素的作用。给荷瘤小鼠接种测试疫苗以监测其对肿瘤转移的影响。我们发现，肿瘤切除手术后腹腔注射雷帕霉素会大幅增加4T1肿瘤的转移活性。台湾国民健康保险研究数据库（NHIRD）数据的流行病学分析表明了这一发现与人类癌症的可能相关性。由于我们之前的研究表明，基于修饰肿瘤细胞裂解物（TCL）脉冲的树突状细胞（DC）癌症疫苗可以有效抑制小鼠肿瘤模型中的转移，我们评估了此类疫苗是否有助于抵消雷帕霉素促进的转移。我们观察到，紫草素在培养中有效诱导4T1细胞的ICD，用紫草素处理的TCL（SK-TCL-DC）脉冲的DC疫苗显著抑制了测试小鼠中雷帕霉素增强的转移和调节性T细胞（Treg）扩增。总之，小鼠（可能还有人类）中的雷帕霉素治疗会促进转移，而基于DC的癌症疫苗治疗可能会抵消这种作用。
