Department of Melanoma Medical Oncology, The Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
J Immunother. 2011 Apr;34(3):279-88. doi: 10.1097/CJI.0b013e31820d2a05.
Unmethylated CpG oligodeoxynucleotides (CpG) are synthetic toll-like receptor 9 agonists that activate innate immune cells and which have been tested as an immune therapy in a number of cancer clinical trials. Although some antitumor immune responses have been reported, so far the majority of studies have failed to show significant clinical responses to CpG. Here we showed that the route of administration is critical to the antitumor activity of CpG. Although intravenous (i.v.) injection of CpG was capable of inducing the activation and expansion of tumor antigen-specific T cells, most of these activated T cells failed to migrate to tumor sites. By contrast, intratumoral (i.t.) injection of CpG led to extensive tumor infiltration of antigen-specific T cells and subsequent tumor suppression. We further showed that very high levels of inflammatory chemokines [regulated upon activation, normal T-cell expressed, and secreted (RANTES), interferon-inducible protein-10 (IP-10), monocyte chemoattractant protein-1, monocyte chemotactic protein (MCP5), macrophage inflammatory proteins (MIP1α, and MIP1β)] were induced in the tumor microenvironment after i.t. CpG injection, compared with administration by the i.v. route. It is interesting to note that, in vivo depletion of plasmacytoid dendritic cells greatly reduced the levels of chemokines induced; also, T-cell accumulation and antitumor effect were impaired. We also showed that i.t. but not i.v. CpG injection induced a broad antigen-specific T-cell response against tumor-derived antigens. Collectively, our data provides evidence that the route of CpG administration is a critical factor in mediating antitumor activity. By inducing localized inflammatory signals at tumor sites, i.t. CpG effectively promotes the migration, activation and function of immune cells, ultimately leading to improved tumor control.
未甲基化的 CpG 寡脱氧核苷酸（CpG）是合成的 Toll 样受体 9 激动剂，可激活先天免疫细胞，并已在许多癌症临床试验中作为免疫疗法进行了测试。尽管已经报道了一些抗肿瘤免疫反应，但到目前为止，大多数研究都未能显示 CpG 对临床有显著反应。在这里，我们发现给药途径对 CpG 的抗肿瘤活性至关重要。尽管静脉注射（i.v.）CpG 能够诱导肿瘤抗原特异性 T 细胞的激活和扩增，但大多数这些激活的 T 细胞未能迁移到肿瘤部位。相比之下，肿瘤内（i.t.）注射 CpG 导致肿瘤内抗原特异性 T 细胞的广泛浸润和随后的肿瘤抑制。我们进一步表明，在 i.t. CpG 注射后，与静脉注射相比，肿瘤微环境中会诱导出非常高水平的炎症趋化因子[激活后调节正常 T 细胞表达和分泌（RANTES）、干扰素诱导蛋白-10（IP-10）、单核细胞趋化蛋白-1、单核细胞趋化蛋白（MCP5）、巨噬细胞炎症蛋白（MIP1α 和 MIP1β）]。有趣的是，注意到体内耗竭浆细胞样树突状细胞会大大降低诱导的趋化因子水平；此外，T 细胞积累和抗肿瘤作用也受到损害。我们还表明，i.t. 但不是 i.v. CpG 注射会诱导针对肿瘤源性抗原的广泛抗原特异性 T 细胞反应。总之，我们的数据提供了证据，表明 CpG 给药途径是介导抗肿瘤活性的关键因素。通过在肿瘤部位诱导局部炎症信号，i.t. CpG 有效地促进免疫细胞的迁移、激活和功能，最终导致肿瘤控制的改善。
