Zhang Mi, Yin Tianquan, Lu Yuan, Feng Huasong
Department of Respiration, General Hospital of Chinese PLA, Beijing, China (mainland).
Department of Emergency, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing, China (mainland).
Med Sci Monit. 2016 Apr 19;22:1309-17. doi: 10.12659/msm.898194.
BACKGROUND Recently, several combined therapeutic strategies and targeted agents have been under investigation for their potential role in lung cancer. The combined administration of dendritic cells (DCs) and immune-adjuvant cytidyl guanosyl oligodeoxynucleotide (CpG-ODN) after cryosurgery has proven to be an effective strategy for treating lung cancer. However, whether the application of CpG-ODN could affect the therapeutic results remained to be further explored. MATERIAL AND METHODS The Lewis lung cancer (LLC)-bearing mice received cryoablation and injection of ex vivo-cultured DCs into the peritumoral zone. Subsequently, CpG-ODN was administered to experimental animals 6 hours, 12 hours, and 24 hours after DC injection. The mice in the control group received coadministration of DCs and CpG-ODN simultaneously. Therapeutic effects were evaluated by survival rates. The resistance to rechallenge of LLC cell was assessed by lung metastasis and in vitro cytotoxicity of splenocytes. Furthermore, T-cell subsets and multiple cytokines (interleukin [IL]-4, -10, and-12; interferon [IFN]-γ; tumor necrosis factor [TNF]-α) in the blood were assessed to elucidate the underlying mechanisms. RESULTS Higher ratios of CD4+ and CD8+ T cells and higher levels of IL-12, IFN-γ, and TNF-α were found in the blood of the mice that received CpG-ODN therapy 12 h after DC injection. The cytotoxicity potency of the splenocytes of these mice was significantly higher compared with the mice in other groups. Moreover, the mice receiving CpG-ODN therapy 12 h after DC injection showed significantly better resistance to rechallenge. Compared with the mice in other groups, the mice receiving CpG-ODN therapy 12 h after DC injection were superior in survival rates and antimetastatic effects. CONCLUSIONS Our study suggested that the therapeutic efficacy was closely associated with CpG-ODN administration in the combined therapeutic protocol of cryoablation, DCs, and immune adjuvant. In situ administration of CpG-ODN 12 h after DC injection might be considered the optimum application.
背景 最近，几种联合治疗策略和靶向药物因其在肺癌中的潜在作用而受到研究。冷冻手术后联合应用树突状细胞（DCs）和免疫佐剂胞苷鸟苷寡脱氧核苷酸（CpG-ODN）已被证明是治疗肺癌的有效策略。然而，CpG-ODN的应用是否会影响治疗效果仍有待进一步探索。
材料与方法 携带Lewis肺癌（LLC）的小鼠接受冷冻消融，并将体外培养的DCs注射到肿瘤周围区域。随后，在DC注射后6小时、12小时和24小时给实验动物施用CpG-ODN。对照组小鼠同时接受DCs和CpG-ODN的联合给药。通过生存率评估治疗效果。通过肺转移和脾细胞的体外细胞毒性评估对LLC细胞再次攻击的抵抗力。此外，评估血液中的T细胞亚群和多种细胞因子（白细胞介素[IL]-4、-10和-12；干扰素[IFN]-γ；肿瘤坏死因子[TNF]-α）以阐明潜在机制。
结果 在DC注射后12小时接受CpG-ODN治疗的小鼠血液中发现较高比例的CD4+和CD8+ T细胞以及较高水平的IL-12、IFN-γ和TNF-α。与其他组的小鼠相比，这些小鼠脾细胞的细胞毒性效力明显更高。此外，在DC注射后12小时接受CpG-ODN治疗的小鼠对再次攻击表现出明显更好的抵抗力。与其他组的小鼠相比，在DC注射后12小时接受CpG-ODN治疗的小鼠在生存率和抗转移效果方面更优。
结论 我们的研究表明，在冷冻消融、DCs和免疫佐剂的联合治疗方案中，治疗效果与CpG-ODN的施用密切相关。DC注射后12小时原位施用CpG-ODN可能被认为是最佳应用。
