Zhang W, He L, Yuan Z, Xie Z, Wang J, Hamada H, Cao X
Department of Immunology, Second Military Medical University, Shanghai, People's Republic of China.
Hum Gene Ther. 1999 May 1;10(7):1151-61. doi: 10.1089/10430349950018148.
Pulsing dendritic cells (DCs) with tumor cell-derived mRNA is regarded as an attractive alternative in the development of DC-based tumor vaccines. Our aim is to improve the therapeutic efficacy of DC-based tumor RNA vaccines by augmenting the preferential chemotaxis of DCs to T cells. Mouse bone marrow-derived DCs were genetically modified with lymphotactin (Lptn) by adenovirus vector, which conferred on DCs preferential chemotaxis to CD4+ and CD8+ T cells (Cao et al., 1998). Lptn gene-modified DCs (Lptn-DCs) were pulsed with tumor mRNA and used for vaccination in the tumor models of 3LL lung carcinoma and B16 melanoma. In both tumor models, immunization with 4 X 10(4) tumor RNA-pulsed Lptn-DCs induced more potent CTL activity, compared with their counterparts, specifically against tumor cells and Mut1 or tyrosinase-related protein 2 (TRP-2) peptide-pulsed RMA-S cells, and rendered the immunized mice resistant to tumor challenge much more effectively. CD8+ T cells were necessary and sufficient to generate the protection of Lptn-DC-based RNA tumor vaccines, and CD4+ T cells were required for the induction of tumor rejection. In the preestablished 3LL and B16 tumor models, vaccination with DC-based or LacZ-DC-based tumor RNA vaccines (2 X 10(5) cells) could reduce pulmonary metastasis and extend survival of tumor-bearing mice, but was less effective than the Lptn-DC counterpart (with 60-80% mice surviving). When the immunizing dose was decreased to 4 X 10(4) cells, Lptn-DC-based tumor vaccines rather than their counterparts were still significantly effective. Our studies provide a potential strategy to improve the efficacy of DC-based vaccines, and a new approach to immunological intervention by chemokines.
用肿瘤细胞衍生的mRNA脉冲处理树突状细胞（DC）被认为是基于DC的肿瘤疫苗开发中一种有吸引力的替代方法。我们的目标是通过增强DC向T细胞的优先趋化作用来提高基于DC的肿瘤RNA疫苗的治疗效果。用腺病毒载体对小鼠骨髓来源的DC进行淋巴趋化因子（Lptn）基因改造，这赋予DC对CD4 +和CD8 + T细胞的优先趋化作用（Cao等人，1998年）。用肿瘤mRNA脉冲处理Lptn基因改造的DC（Lptn-DC），并将其用于3LL肺癌和B16黑色素瘤肿瘤模型的疫苗接种。在这两种肿瘤模型中，与对照相比，用4×10⁴个肿瘤RNA脉冲处理的Lptn-DC进行免疫诱导了更强的CTL活性，特别是针对肿瘤细胞以及Mut1或酪氨酸酶相关蛋白2（TRP-2）肽脉冲处理的RMA-S细胞，并使免疫小鼠更有效地抵抗肿瘤攻击。CD8 + T细胞对于产生基于Lptn-DC的RNA肿瘤疫苗的保护作用是必要且充分的，而CD4 + T细胞是诱导肿瘤排斥所必需的。在预先建立的3LL和B16肿瘤模型中，用基于DC或基于LacZ-DC的肿瘤RNA疫苗（2×10⁵个细胞）进行疫苗接种可以减少肺转移并延长荷瘤小鼠的生存期，但效果不如Lptn-DC对照（60 - 80%的小鼠存活）。当免疫剂量降低到4×10⁴个细胞时，基于Lptn-DC的肿瘤疫苗而非对照疫苗仍然显著有效。我们的研究提供了一种提高基于DC的疫苗疗效的潜在策略，以及一种通过趋化因子进行免疫干预的新方法。
