Zheng Yi, Hu Bicheng, Xie Shenggao, Chen Xiaofan, Hu Yuqian, Chen Wanping, Li Shanshan, Hu Bo
The Central Laboratory, Guangming New District People's Hospital, Shenzhen, China; School of Laboratory Medicine, Hubei University of Chinese Medicine, Wuhan, China.
Institute of Virology, School of Medicine, State Key Laboratory of Virology, Wuhan University, Wuhan, China.
Cytotherapy. 2017 May;19(5):617-628. doi: 10.1016/j.jcyt.2017.01.008. Epub 2017 Feb 16.
Cervical cancer constitutes a major problem in women's health worldwide, but the efficacy of the standard therapy is unsatisfactory. Cytokine-induced killer (CIK) cells exhibit antitumor activity against a variety of malignancies in preclinical models and have proven safe and effective in clinical trials. However, current CIK therapy has limitations and needs to be improved to meet the clinical requirements. The aim of this study was to investigate whether suppressing the expression of cytokine signaling 1 (SOCS1) in dendritic cells (DCs) can shorten in vitro CIK culture time and improve its antitumor efficacy.
DCs were pre-cultured for 3 days before infected with adenovirus-mediated-SOCS1 short hairpin RNA (Ad-sh-SOCS1) and pulsed with CTL epitope peptides E7. The DCs infected by Ad-sh-SOCS1 (gmDCs) and CIKs were then co-cultured for 5 or 9 days, and CIK proliferation and antitumor activity were evaluated both in vitro and in vivo.
Our data show that gmDCs significantly stimulated the expansion of co-cultured CIKs and increased the secretion of interferon-γ and interleukin-12. Moreover, gmDCs-activated CIKs showed higher cytotoxic activity against TC-1 cells expressing HPV16E6 and E7. Our in vivo study showed that the mice infused with gmDCs-activated CIKs on day 10 had an increased survival rate and prolonged survival time compared with the controls.
Taken together, these results indicate that DCs modified by adenovirus-mediated SOCS1 silencing can promote CIKs expansion and enhance the efficacy of antitumor immunotherapy both in vitro and in vivo, which represents an effective therapeutic approach for cervical cancer and other tumors.
宫颈癌是全球女性健康领域的一个重大问题，但标准疗法的疗效并不理想。细胞因子诱导的杀伤细胞（CIK）在临床前模型中对多种恶性肿瘤具有抗肿瘤活性，且在临床试验中已证明其安全有效。然而，目前的CIK疗法存在局限性，需要改进以满足临床需求。本研究的目的是探讨抑制树突状细胞（DC）中细胞因子信号传导1（SOCS1）的表达是否能缩短体外CIK培养时间并提高其抗肿瘤疗效。
DC先预培养3天，然后用腺病毒介导的SOCS1短发夹RNA（Ad-sh-SOCS1）感染，并与细胞毒性T淋巴细胞（CTL）表位肽E7一起脉冲处理。然后将Ad-sh-SOCS1感染的DC（gmDC）与CIK共培养5天或9天，并在体外和体内评估CIK的增殖和抗肿瘤活性。
我们的数据表明，gmDC显著刺激了共培养的CIK的扩增，并增加了干扰素-γ和白细胞介素-12的分泌。此外，gmDC激活的CIK对表达人乳头瘤病毒16E6和E7的TC-1细胞显示出更高的细胞毒性活性。我们的体内研究表明，与对照组相比，在第10天注入gmDC激活的CIK的小鼠存活率提高，生存时间延长。
综上所述，这些结果表明，通过腺病毒介导的SOCS1沉默修饰的DC可以促进CIK的扩增，并在体外和体内增强抗肿瘤免疫治疗的疗效，这代表了一种针对宫颈癌和其他肿瘤的有效治疗方法。
