Department of Histology and Embryology, Tongji University School of Medicine, Shanghai, China.
PLoS One. 2013 Sep 2;8(9):e73952. doi: 10.1371/journal.pone.0073952. eCollection 2013.
CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4(+) CD25(+) Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4(+), CD8(+) T cells and CD11c(+) DCs within the tumor, coincident with marked induction of tumor-specific CD8(+) cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.
CCL21 已知可吸引树突状细胞 (DC) 和 T 细胞，从而可能逆转肿瘤介导的免疫抑制。调节性 T 细胞 (Tregs) 的大量浸润肿瘤可防止辅助性免疫应答的成功发展。在这项研究中，我们研究了使用抗 CD25 单克隆抗体 (mAb) 在肿瘤微环境中消除 CD4+CD25+Tregs 是否能够增强 CCL21 介导的小鼠肝细胞癌 (HCC) 模型中的抗肿瘤免疫。我们发现，CCL21 与抗 CD25 mAb (PC61) 联合使用可提高抗肿瘤疗效并延长生存期，不仅抑制肿瘤血管生成和细胞增殖，而且还导致肿瘤内 CD4+、CD8+T 细胞和 CD11c+DC 的频率显著增加，同时在局部肿瘤部位显著诱导肿瘤特异性 CD8+细胞毒性 T 淋巴细胞 (CTL)。肿瘤内免疫反应伴随着 IL-12 和 IFN-γ 的大量分泌，但 IL-10 和 TGF-β1 的免疫抑制介质的释放减少。结果表明，在肿瘤微环境中耗尽 Tregs 可增强 CCL21 介导的抗肿瘤免疫，CCL21 联合抗 CD25 mAb 可能是一种更有效的免疫疗法，可促进肿瘤排斥。
