Relationship of TGF‐β1 and Smad7 expression with decreased dendritic cell infiltration in liver gastrointestinal cancer metastasis

Abstract

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.