CIK细胞载体运载reovirus溶瘤病毒在靶向抗肿瘤效应中的作用及机制研究

Oncolytic viruses are a research hotspot due to their prospects in treatment of tumors. Many types of oncolytic viruses are already used in clinical trials, and especially the wide-type reovirus enters phase III clinical trials. In order to improve the oncolytic effect of reovirus after intravenous administration, CIK cells with tumor-chemotaxis and killing effect were selected as its carrier, which would help reovirus to overcome the barriers in clinical trials. We aim to: (1) evaluate whether CIK is a suitable carrier for reovirus, and optimize the conditions for CIK to carry reovirus; (2) investigate whether CIK can help reovirus to overcome the barriers and thus improve its oncolytic effect, and discuss the mechanism; (3) investigate whether CIK and reovirus have targeted killing effect on cancer stem cell. Studies on these three problems will provide us theoretical and experimental foundation for exploring suitable carriers of reovirus, for the clinical application of CIK, and for understanding the new targets of reovirus' oncolytic effect.

溶瘤病毒作为肿瘤治疗的新策略已成为当前的研究热点，已有多种溶瘤病毒进入了临床实验研究中，其中野生型reovirus已进入III期临床实验，为提高reovirus静脉应用的疗效，本研究拟选用CIK细胞作为reovirus的细胞载体，期望利用具有肿瘤趋化及杀伤作用的CIK细胞来帮助reovirus克服临床研究中所面临的障碍。本项目拟解决的关键问题包括（1）评价CIK是否是reovirus适合的细胞载体，优化CIK装载reovirus的条件；（2）分析CIK能否帮助reovirus克服不足来促进溶瘤效应并探讨可能机制；（3）讨论CIK及reovirus能否对人结肠癌CSC发挥杀伤作用。对以上问题进行研究将为寻找reovirus适合的细胞载体提供理论依据和实验基础，为CIK的临床应用提供新思路，并为研究CIK及reovirus联合抗肿瘤效应的新靶点提供理论依据。

溶瘤病毒作为肿瘤治疗的新策略已成为当前的研究热点，为提高reovirus静脉应用的疗效，本项目聚焦于以reovirus为中心的联合治疗策略， 提出了reovirus与细胞因子诱导的杀伤细胞（CIK）或与cetuximab联合后可通过互补或协同作用而诱导更强的抗肿瘤效应的假设。本研究通过对该联合治疗策略的作用及机制进行探讨，以期为肿瘤联合治疗提供新策略。研究发现reovirus可通过在肿瘤细胞内大量复制增殖而发挥显著的溶瘤效应，而对CIK及NK细胞存活率影响轻微，且reovirus感染后可促进CIK及NK细胞的细胞毒效应；CIK适合做为reovirus的运载细胞，可在中和抗体存在下将病毒传递给肿瘤细胞。此外，reovirus预处理NK细胞降低了抗体依赖的细胞介导的细胞毒作用（ADCC）达到最大细胞毒性所需的抗体量，reovirus促进ADCC效应与NK细胞释放穿孔素及FasL增高有关；Reovirus联合cetuximab治疗活化了裸鼠体内的NK细胞，增加功能性NK细胞数量来延缓荷瘤裸鼠肿瘤生长。这些研究发现为我们进一步深入研究基于reovirus的联合抗肿瘤治疗策略奠定了理论及实验基础, 具有重要的学术价值和应用前景。