Induction of CD4+ T cell-dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells
Induction of CD4+ T cell-dependent antitumor immunity by TAT-mediated tumor antigen delivery into dendritic cells
复制标题
DOI：
10.1172/jci200215399
复制
发表时间：
2002-06-01
影响因子：
15.9
通讯作者：
Wang, RF
中科院分区：
文献类型：
--
作者：
Wang, HY;Fu, T;Wang, RF
基于树突状细胞(DC)的免疫治疗是预防和治疗包括癌症在内的许多疾病的一种有前途的方法，但目前的策略在临床和临床前研究中仅取得了有限的成功。以前的研究已经证明，从HIV TAT蛋白衍生的TAT多肽具有将多肽或蛋白质转导到各种细胞中的能力。在这里，我们描述了使用TAT介导的T细胞多肽递送到树突状细胞来延长抗原呈递和增强T细胞反应。用来自人Trp2蛋白的抗原肽冲击的DC免疫小鼠产生了对B16肿瘤的部分保护性免疫，而负载TAT-Trp2多肽的DC免疫小鼠产生了完全的保护性免疫，并在3天的肿瘤模型中显著抑制了肺转移。尽管DC/Trp2和DC/Tat-Trp2免疫均能增加K-b/Trp2四聚体检测到的Trp2特异性CD8(+)T细胞的数量，但DC/Tat-Trp2诱导的T细胞活性是DC/Trp2诱导的3-10倍。此外，T细胞亚群的抗体去除实验以及各种基因敲除小鼠的实验表明，抗肿瘤免疫需要CD4(+)和CD8(+)T细胞。这些结果表明，TAT介导的抗原递送系统可能在癌症治疗中有重要的临床应用。
Dendritic cell-based (DC-based) immunotherapy represents a promising approach to the prevention and treatment of many diseases, including cancer, but current strategies have met with only limited success in clinical and preclinical studies. Previous studies have demonstrated that a TAT peptide derived from the HIV TAT protein has the ability to transduce peptides or proteins into various cells. Here, we describe the use of TAT-mediated delivery of T cell peptides into DCs to prolong antigen presentation and enhance T cell responses. While immunization of mice with DCs pulsed with an antigenic peptide derived from the human TRP2 protein generated partial protective immunity against B16 tumor, immunization with DCs loaded with a TAT-TRP2 peptide resulted in complete protective immunity, as well as significant inhibition of lung metastases in a 3-day tumor model. Although both DC/TRP2 and DC/TAT-TRP2 immunization increased the number of TRP2-specific CD8(+) T cells detected by K-b/TRP2 tetramers, T cell activity elicited by DC/TAT-TRP2 was three-to tenfold higher than that induced by DC/TRP2. Furthermore, both CD4(+) and CD8(+) T cells were required for antitumor immunity demonstrated by experiments with antibody depletion of subsets of T cells, as well as with various knockout mice. These results suggest that a TAT-mediated antigen delivery system may have important clinical applications for cancer therapy.