The Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmacy, Binzhou Medical University, Yantai 264003, China.
Collega of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University, Yantai 264003, China.
Eur J Pharm Sci. 2018 Mar 1;114:228-237. doi: 10.1016/j.ejps.2017.12.020. Epub 2017 Dec 24.
Human umbilical vein endothelial cell (HUVEC) vaccine has been proved as an effective whole-cell vaccine, but the modest therapeutic anti-tumor efficiency limits its clinical use. Various antigen forms, including paraformaldehyde-fixed HUVEC, glutaraldehyde-fixed HUVEC, HUVEC lysate and live HUVEC, have been intensively used in HUVEC vaccine preparation, however, the most effective antigen form has not yet been identified. In the present study, these four commonly used antigen forms were used to prepare vaccines named Para-Fixed-EC, Glu-Fixed-EC, Lysate-EC, and Live-EC respectively, and the anti-tumor efficacy of these four vaccines was investigated. Results showed that Live-EC exhibited the most favorable anti-tumor growth and metastasis effects among the four vaccines in both H22 hepatocellular carcinoma and Lewis lung cancer models. High titer anti-HUVEC antibodies were detected in Live-EC immunized mice sera, and the immune sera of Live-EC group could significantly inhibit HUVEC proliferation and tube formation. Moreover, T cells isolated from Live-EC immunized mice exhibited strong cytotoxicity against HUVEC cells, with an increasing IFN-γ and decreasing Treg production in Live-EC immunized mice. Finally, CD31 immunohistochemical analysis of the excised tumors verified a significant reduction in vessel density after Live-EC vaccination, which was in accordance with the anti-tumor efficiency. Taken together, all the results proved that live HUVEC was the most effective antigen form to induce robust HUVEC specific antibody and CTL responses, which could lead to the significant inhibition of tumor growth and metastasis. We hope the present findings would provide a rationale for the further optimization of HUVEC vaccine.
人脐静脉内皮细胞（HUVEC）疫苗已被证明是一种有效的全细胞疫苗，但适度的治疗抗肿瘤效率限制了其临床应用。各种抗原形式，包括甲醛固定的 HUVEC、戊二醛固定的 HUVEC、HUVEC 裂解物和活的 HUVEC，已被广泛用于 HUVEC 疫苗的制备，但最有效的抗原形式尚未确定。在本研究中，分别使用这四种常用的抗原形式来制备疫苗，命名为 Para-Fixed-EC、Glu-Fixed-EC、Lysate-EC 和 Live-EC，并研究了这四种疫苗的抗肿瘤疗效。结果表明，在 H22 肝癌和 Lewis 肺癌模型中，活的 HUVEC 表现出最有利的抗肿瘤生长和转移作用。在活的 HUVEC 免疫小鼠血清中检测到高滴度的抗 HUVEC 抗体，活的 HUVEC 组的免疫血清可显著抑制 HUVEC 的增殖和管腔形成。此外，从活的 HUVEC 免疫小鼠中分离出的 T 细胞对 HUVEC 细胞表现出强烈的细胞毒性，活的 HUVEC 免疫小鼠中 IFN-γ的产生增加，Treg 的产生减少。最后，对切除的肿瘤进行 CD31 免疫组织化学分析证实，活的 HUVEC 疫苗接种后血管密度显著降低，与抗肿瘤效率一致。综上所述，所有结果均证明活的 HUVEC 是诱导强大的 HUVEC 特异性抗体和 CTL 反应的最有效抗原形式，可显著抑制肿瘤生长和转移。我们希望本研究结果能为进一步优化 HUVEC 疫苗提供依据。
