CCL22／CCR4信号通路在原发性肝癌局部免疫逃逸中的作用

CCL22/CCR4 signaling induces immune escape in hepatocellular carcinoma

目的探讨CCL22／CCR4信号通路在原发性肝癌组织中CD4＋CD25＋调节性T细胞（Tregs）募集及肝癌局部免疫逃逸中的作用。方法取肝癌、非肝癌组织样本各30例制成单细胞悬液。离心后收集上清，ELISA法检测趋化因子CCL22、白介素-2（IL-2）、白介素-10（IL-10）和转化生长因子．B（TGF—B）水平。分离出组织中的淋巴细胞，流式细胞仪检测CD4’CD25’Tregs水平及其表面受体CCRd的表达。结果肝癌组织标本中CCL22表达水平为（920．1±180．1）ng／L，明显高于非肝癌组织[（227．2±108．6）ng／L；P〈0．05]。肝癌组织中CD4＋CD25＋Tregs占CIM＋T细胞的百分比为（13．3±4．O）％，明显高于非肝癌组织[（5．2±2．8）ng/L；P〈0．（15]，且表面受体CCR4呈高表达，百分比为（8．8±3．0）％。随着肿瘤临床TNM分期的进展，肝癌组织中CIM’CD25’Treg、CIM’CD25‘CCR4’Tregs数量增多，且与组织标本中CCL22水平呈正相关。与非肝癌组比较，肝癌组织标本中IL一2显著降低（P〈0．05），IL—10和TGF—B水平显著升高（P〈0．05）。结论肝癌组织可分泌大量的CCL22，通过CCL22／CCRd信号通路募集CD4’CD25’Tregs聚集在肿瘤部位，通过分泌大量的IL-10和TGF．8，同时抑制IL-2分泌引起肝癌局部免疫逃逸。抑制CCL22／CCB4信号通路有可能成为肝癌免疫治疗的新靶点。

Objective To investigate the regulation of CCL22/CCR4 signaling on CD4 ＋ CD25 ＋ reg- ulatory T cells （Tregs） and immune escape in hepatocellular carcinoma （HCC）. Methods CCL22, inter- leukin-2 （IL-2）, transforming growth factor-β （TGF-[3） , and interleukin-lO （IL-10） levels in tumor tissue of 30 HCC patients were determined by ELISA. Tumor infiltrating lymphocytes were isolated and assayed by flow cytometry to evaluate the change of CD4 ＋ CD25 ＋ Tregs in tumor tissue, and CCR4 in CD4 ＋ CD25 ＋ Tregs were detected. Results The CCL22 level in tumor tissue was obviously increased. The level of CCI22 in tumor tissue was （920.1 ＋ 180.1 ）ng/L, which was significantly higher than that in non-tumor tis- sue E （ 227.2 ＋ 108.6 ） ng/L ; P 〈 0.051. The tumor infiltrating CIM ＋ CD25 ＋ Tregs was obviously increased, reaching approximately to （13.3±4.0）%, and the CCR4 expression in CD4＋ CD25 ＋ Tregs increased to （8.8 ± 3.0） %. Along with progression in clinical TNM staging, the levels of CD4 ＋ CD25 ＋ Tregs and CIM ＋ CD25 ＋ CCR4 ＋ Tregs in tumor tissue increased, and were correlated with the CCI_22 level. IL-2 level in tumor tissue was decreased, but TGF-β and IL-10 levels were increased. HCC tissue can secrete a large amount of CCL22 that could recruit CD4 ＋ CD25 ＋ Tregs to tumor tissue by activating CCL22/CCR4 signa- ling. CD4 ＋ CD25 ＋ Tregs played an important role in the immune escape of HCC by releasing plenty of TGF- β and IL-10 and inhibiting IL-2 secretion. Conclusion This study validates CCL22/CCR4 as therapeutic targets in immunotherapy for HCC.