Peritumoral CpG DNA elicits a coordinated response of CD8 T cells and innate effectors to cure established tumors in a murine colon carcinoma model
Peritumoral CpG DNA elicits a coordinated response of CD8 T cells and innate effectors to cure established tumors in a murine colon carcinoma model
复制标题
DOI：
10.4049/jimmunol.169.7.3892
复制
发表时间：
2002-10-01
影响因子：
4.4
通讯作者：
Hartmann, G
中科院分区：
文献类型：
--
作者：
Heckelsmiller, K;Rall, K;Hartmann, G
脊椎动物的免疫系统能够基于未甲基化的CpG基序的存在来检测细菌DNA。我们研究了含CpG基序的寡脱氧核苷酸（CpG ODN）对BALB/c小鼠结肠癌模型的治疗潜力。通过皮下注射诱导肿瘤注射同系C26细胞或Renca肾癌细胞作为对照。单独注射CpG ODN或与照射的肿瘤细胞组合注射不能保护小鼠抵抗随后的肿瘤攻击。相反，每周将CpG ODN注射到已经建立的肿瘤边缘导致肿瘤消退和小鼠完全治愈。注射部位是关键的，因为在远处注射CpG ODN无效。具有两个双侧C26肿瘤的小鼠在瘤周注射一个肿瘤后排斥两个肿瘤，表明系统性免疫应答的发展。在同时携带C26肿瘤和Renca肿瘤的小鼠中证明了免疫应答的肿瘤特异性。在瘤周CpG治疗后排斥肿瘤的小鼠保持无肿瘤，并且被保护免于用相同的肿瘤细胞而不是用另一种肿瘤再攻击，这证明了长期记忆。肿瘤特异性CD8 T细胞以及先天效应细胞有助于治疗的抗肿瘤活性。总之，瘤周CpG ODN单一疗法激发了强烈的CD8 T细胞应答和先天效应机制，这些机制似乎共同作用以克服免疫系统对生长的肿瘤的无应答性。
The immune system of vertebrates is able to detect bacterial DNA based on the presence of unmethylated CpG motifs. We examined the therapeutic potential of oligodeoxynucleotides with CpG motifs (CpG ODN) in a colon carcinoma model in BALB/c mice. Tumors were induced by s.c. injection of syngeneic C26 cells or Renca kidney cancer cells as a control. Injection of CpG ODN alone or in combination with irradiated tumor cells did not protect mice against subsequent tumor challenge. In contrast, weekly injections of CpG ODN into the margin of already established tumors resulted in regression of tumors and complete cure of mice. The injection site was critical, since injection of CpG ODN at distant sites was not effective. Mice with two bilateral C26 tumors rejected both tumors upon peritumoral injection of one tumor, indicating the development of a systemic immune response. The tumor specificity of the immune response was demonstrated in mice bearing a C26 tumor and a Renca tumor at the same time. Mice that rejected a tumor upon peritumoral CpG treatment remained tumor free and were protected against rechallenge with the same tumor cells, but not with the other tumor, demonstrating long term memory. Tumor-specific CD8 T cells as well as innate effector cells contributed to the antitumor activity of treatment. In conclusion, peritumoral CpG ODN monotherapy elicits a strong CD8 T cell response and innate effector mechanisms that seem to act in concert to overcome unresponsiveness of the immune system toward a growing tumor.