Department of General and Clinical Pathology, Medical Faculty, Trakia University, Stara Zagora.
APMIS. 2013 Oct;121(10):967-75. doi: 10.1111/apm.12096. Epub 2013 Sep 2.
Immune responses and their modulation within the liver are critical to the outcome of liver malignancies. In late-stage tumors, secreted TGF-β promotes oncogenic functions and can confer tolerogenicity to some immune cells like DCs. The TGF-β signaling pathway is involved in the control of several biological processes, including immunosurveillance. The aim of the present study was to assess CD1a(+) and CD83(+) DCs and to evaluate the impact of TGF-β pathway on DCs maturation and distribution in the liver metastases from gastric and colorectal tumors. The percentage of CD83(+) DCs in the liver tissue, surrounding metastasis and in the metastasis-free liver was measured by flow cytometry, and TGF-β levels were assessed in the tissue supernatant from the peritumoral liver after mononuclear cell isolation and in the sera of the same patients. CD1a(+) and CD83(+) DCs were observed in the tumor stroma and border. Out of 73 patients, there was cytoplasmic reactivity: of TGF-β1 in 37 (50.7%); of Smad4 in 62 (84.9%); of Smad7 in 46 (63%), and of TGFβRII in 39 (53.4%) of the metastases. The TGF-β1 expression in tumor cell cytoplasm correlated with low CD1a(+) and low CD83(+) DCs infiltration. The tissue levels of TGF-β1, measured by ELISA in the supernatant were significantly increased in metastases than in normal liver. Using a two-color FACS analysis, we found that the percentage of HLA-DR(+) CD83(+) DCs in metastases was significantly decreased as compared with metastasis-free liver tissue. In conclusion, the positive and negative correlations between the mediators from the TGF-β pathway implied the existence of imbalance and suppression of this cytokine activity. The presence of increased TGF-β expression by immunohistochemistry in tumor cells was confirmed by detection of increased TGF-β tissue level in the supernatant from the tissue homogenate. The observation of low numbers of CD1a(+) and CD83(+) DCs in tumor stroma correlated with TGF-β overexpression in tumor cells, a fact that well documents the immunosuppressive role of TGF-β in metastasis development. The increased percentage of CD83(+) DCs in the peritumoral tissue supposes that there could be active recruitment or local differentiation of DCs in the metastasis border, but inside the tumor the immune cells recruitment and activity are suppressed by TGF-β and by other cytokines.
肝脏中的免疫反应及其调节对肝脏恶性肿瘤的结局至关重要。在晚期肿瘤中，分泌的 TGF-β 促进致癌功能，并使某些免疫细胞（如 DC）具有耐受性。TGF-β 信号通路参与控制包括免疫监视在内的几种生物过程。本研究的目的是评估 CD1a(+) 和 CD83(+) DC，并评估 TGF-β 途径对胃和结直肠肿瘤肝转移中 DC 成熟和分布的影响。通过流式细胞术测量肝组织、肿瘤周围转移和无转移肝中 CD83(+) DC 的百分比，并在单核细胞分离后的肿瘤周围肝组织上清液和同一患者的血清中评估 TGF-β 水平。在肿瘤基质和边界中观察到 CD1a(+) 和 CD83(+) DC。在 73 名患者中，有细胞质反应：TGF-β1 在 37 名患者（50.7%）中；Smad4 在 62 名患者（84.9%）中；Smad7 在 46 名患者（63%）中；TGFβRII 在 39 名患者（53.4%）中。肿瘤细胞质中 TGF-β1 的表达与低 CD1a(+) 和低 CD83(+) DC 浸润相关。通过 ELISA 在上清液中测量的 TGF-β1 的组织水平在转移中明显高于正常肝。使用双色 FACS 分析，我们发现与无转移肝组织相比，转移中 HLA-DR(+) CD83(+) DC 的百分比显著降低。总之，TGF-β 途径的介质之间的正相关和负相关表明存在这种细胞因子活性的失衡和抑制。通过检测组织匀浆上清液中 TGF-β 组织水平的增加，证实了肿瘤细胞中 TGF-β 表达的增加。在肿瘤细胞中 TGF-β 过表达的情况下，在肿瘤基质中观察到低数量的 CD1a(+) 和 CD83(+) DC，这很好地证明了 TGF-β 在转移发展中的免疫抑制作用。在肿瘤周围组织中 CD83(+) DC 百分比的增加表明，在转移边界处可能存在 DC 的主动募集或局部分化，但在肿瘤内，免疫细胞的募集和活性受到 TGF-β 和其他细胞因子的抑制。
