Shanghai 10th People's Hospital Affiliated to Tongji University, Shanghai 200072, PR China.
Int J Oncol. 2011 Jul;39(1):245-53. doi: 10.3892/ijo.2011.1004. Epub 2011 Apr 13.
α-fetoprotein (AFP), a tumor-associated antigen for hepatocellular carcinoma (HCC), is an established biomarker for HCC. In this study, we created a lentivirus expressing the AFP antigen and investigated the anti-tumor activity of AFP-specific CD8+ T cells, with and without CD4+ T cells, which were activated by either AFP peptide-pulsed or Lenti-AFP-engineered Dendritic cells (DCs) in vitro and in vivo. AFP-specific T cells could efficiently kill HepG2 HCC cells, and produced IL-2, IFN-γ, TNF-α, perforin and granzyme B, with minimal production of IL-10 (a negative regulator of T cell activation). Both strategies activated AFP-specific T cells, but the lentiviral strategy was superior by several measures. Data also support an impact of CD4+ T cells in supporting anti-tumor activity. In vivo studies in a xenograft HCC tumor model also showed that AFP-specific T cells could markedly suppress HCC tumor formation and morbidity in tumor-bearing nude mice, as well as regulate serum levels of related cytokines and anti-tumor molecules. In parallel with human in vitro T cell cultures, the in vivo model demonstrated superior anti-tumor effects and Th1-skewing with Lenti-AFP-DCs. This study supports the superiority of a full-length antigen lentivirus-based DCs vaccine strategy over peptides, and provides new insight into the design of DCs-based vaccines.
甲胎蛋白（AFP）是肝癌（HCC）的肿瘤相关抗原，是 HCC 的一种既定生物标志物。本研究构建了表达 AFP 抗原的慢病毒，并研究了 AFP 特异性 CD8+T 细胞的抗肿瘤活性，这些细胞是通过 AFP 肽脉冲或 Lenti-AFP 工程化树突状细胞（DC）在体外和体内激活的，同时有或没有 CD4+T 细胞。AFP 特异性 T 细胞可以有效杀伤 HepG2 HCC 细胞，并产生 IL-2、IFN-γ、TNF-α、穿孔素和颗粒酶 B，同时很少产生 IL-10（T 细胞激活的负调节剂）。两种策略都能激活 AFP 特异性 T 细胞，但慢病毒策略在多个方面更具优势。数据还支持 CD4+T 细胞在支持抗肿瘤活性方面的作用。在 HCC 肿瘤异种移植模型的体内研究中也表明，AFP 特异性 T 细胞可以显著抑制荷瘤裸鼠 HCC 肿瘤的形成和发病率，并调节相关细胞因子和抗肿瘤分子的血清水平。与人类体外 T 细胞培养平行，体内模型显示 Lenti-AFP-DC 具有更好的抗肿瘤作用和 Th1 偏向性。本研究支持全长抗原慢病毒 DC 疫苗策略优于肽的优势，并为 DC 疫苗的设计提供了新的见解。
