Minigene Pharmacy Laboratory, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China.
Int Immunopharmacol. 2011 Dec;11(12):2200-7. doi: 10.1016/j.intimp.2011.10.001. Epub 2011 Oct 18.
Therapeutic vaccination with dendritic cells (DCs) pulsed with tumor cell lysate vaccine (H-D) represents an attractive approach for hepatocellular carcinoma (HCC) treatment. However, the efficacy of this approach is not most satisfactory for the low levels of T helper 1 (Th1)-type cytokines secretion and weak T cell responses. In this study, in order to increase the potency of H-D, two tandem repeats of microbial HSP70 peptide epitope 407-426 (2mHSP70(407-426), M2) which has been demonstrated to be effective in enhancing DC maturation were applied. The DC vaccine (HM-D) which was HCC tumor cell lysate pulsed with M2 was developed. Nevertheless, the immunotherapeutic effect was still not satisfactory enough even some promotion was obtained. Therefore, OK-432 (OK), which is a useful anti-cancer agent and effectively in stimulating DC maturation, was introduced to HM-D. Our results demonstrated that treatment with the improved DC vaccine which was tumor cell lysate pulsed with M2 and OK (HMO-D), compared with H-D and HM-D, significantly increased cell surface markers (MHC-I and II, CD40, CD80, CD86 and CD11c) expression on DCs, enhanced Th1-type cytokines (IL-12, TNF-α and IFN-γ) production but not Th2-type cytokine (IL-5) production, induced remarkable high levels of lymphocytes proliferation and CD8(+) cytotoxic T-lymphocyte (CTL). Furthermore, immunization with HMO-D effectively reduced tumor progression and enhanced the survival of mice with H22 tumors. Besides, we also found that the capability of M2 in inducing the Th1 cytokines was stronger than OK. In view of these results, HMO-D vaccination provided a novel immunotherapeutic approach for the treatment of HCC.
用肿瘤细胞裂解物疫苗（H-D）脉冲处理树突状细胞（DC）的治疗性疫苗接种代表了治疗肝细胞癌（HCC）的一种有吸引力的方法。然而，由于 Th1 型细胞因子分泌水平低和 T 细胞反应较弱，这种方法的疗效并不最令人满意。在这项研究中，为了提高 H-D 的效力，应用了已被证明能有效增强 DC 成熟的微生物 HSP70 肽表位 407-426 的两个串联重复（2mHSP70（407-426），M2）。开发了用 M2 脉冲处理 HCC 肿瘤细胞裂解物的 DC 疫苗（HM-D）。然而，即使获得了一些促进作用，免疫治疗效果仍然不够令人满意。因此，引入了 OK-432（OK），这是一种有效的抗癌药物，能有效刺激 DC 成熟。我们的研究结果表明，与 H-D 和 HM-D 相比，用 M2 和 OK 脉冲处理的改良 DC 疫苗（HMO-D）治疗，显著增加了 DC 表面标志物（MHC-I 和 II、CD40、CD80、CD86 和 CD11c）的表达，增强了 Th1 型细胞因子（IL-12、TNF-α 和 IFN-γ）的产生，但不增强 Th2 型细胞因子（IL-5）的产生，诱导了显著高水平的淋巴细胞增殖和 CD8+细胞毒性 T 淋巴细胞（CTL）。此外，用 HMO-D 免疫可有效抑制肿瘤进展，提高荷 H22 肿瘤小鼠的存活率。此外，我们还发现 M2 诱导 Th1 细胞因子的能力强于 OK。鉴于这些结果，HMO-D 疫苗接种为治疗 HCC 提供了一种新的免疫治疗方法。
