Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity.
Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity.
复制标题
基于由粒细胞巨噬细胞集落刺激因子基因转导的侧群细胞的治疗性疫苗接种可引发有效的抗肿瘤免疫。
DOI：
10.1038/cgt.2016.80
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Tani K
中科院分区：
文献类型：
--
作者：
Sakamoto C;Kohara H;Inoue H;Narusawa M;Ogawa Y;Hirose-Yotsuya L;Miyamoto S;Matsumura Y;Yamada K;Takahashi A;Tani K
在癌症免疫疗法中，粒细胞-巨噬细胞集落刺激因子（GM-CSF）基因转导的肿瘤细胞疫苗（GVAX）疗法似乎很有前途，并已在多项临床试验中显示出安全有效。然而，单独的GVAX疗法的抗肿瘤功效在某些情况下是有限的。在这里，我们表明，靶向癌症干细胞（CSC）的GVAX治疗在重现正常免疫系统的同基因免疫活性小鼠中基本上抑制了肿瘤发展。从4 T1小鼠乳腺癌细胞系中分离CSC作为侧群（SP）细胞，并用非传染性仙台病毒（4 T1-SP/GM）递送的GM-CSF基因转导。皮下注射4 T1-SP/GM的致瘤性受损依赖于与CD 4 + T细胞和自然杀伤细胞一致的CD 8 + T细胞。与用未转导的4 T1-SP细胞或非SP（4 T1-NSP/GM）细胞的辐射细胞处理的小鼠相比，用辐射的4 T1-SP/GM细胞治疗性接种的小鼠显著抑制皮下移植的4 T1-SP细胞的肿瘤发展。肿瘤抑制伴随着成熟树突状细胞在疫苗接种部位的大量积累和辅助性T细胞1型偏斜的全身细胞免疫。我们的研究结果表明，CSC细胞为基础的GVAX免疫治疗可能是临床上有用的诱导有效的肿瘤特异性抗肿瘤免疫。
Among cancer immunotherapies, granulocyte–macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8+ T cells in concert with CD4+ T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity.