| Autor: |
Jasinski-Bergner S; Institute of Medical Immunology; Martin Luther University Halle-Wittenberg ; Halle, Germany., Stoehr C; Institute of Pathology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Bukur J; Institute of Medical Immunology; Martin Luther University Halle-Wittenberg ; Halle, Germany., Massa C; Institute of Medical Immunology; Martin Luther University Halle-Wittenberg ; Halle, Germany., Braun J; Institute of Molecular Medicine; Martin Luther University Halle-Wittenberg ; Halle, Germany., Hüttelmaier S; Institute of Molecular Medicine; Martin Luther University Halle-Wittenberg ; Halle, Germany., Spath V; Institute of Pathology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Wartenberg R; Institute of Pathology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Legal W; Clinic of Urology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Taubert H; Clinic of Urology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Wach S; Clinic of Urology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Wullich B; Clinic of Urology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Hartmann A; Institute of Pathology; Friedrich Alexander University Erlangen-Nuremberg ; Erlangen, Germany., Seliger B; Institute of Medical Immunology; Martin Luther University Halle-Wittenberg ; Halle, Germany. |
| Abstrakt: |
In human tumors of distinct origin including renal cell carcinoma (RCC), the non-classical human leukocyte antigen G (HLA-G) is frequently expressed, thereby inhibiting the cytotoxic activity of T and natural killer (NK) cells. Recent studies demonstrated a strong post-transcriptional gene regulation of the HLA-G by miR-152, -148A, -148B and -133A. Standard methods were applied to characterize the expression and function of HLA-G, HLA-G-regulatory microRNAs (miRs) and the immune cell infiltration in 453 RCC lesions using a tissue microarray and five RCC cell lines linking these results to clinical parameters. Direct interactions with HLA-G regulatory miRs and the HLA-G 3' untranslated region (UTR) were detected and the affinities of these different miRs to the HLA-G 3'-UTR compared. qPCR analyses and immunohistochemical staining revealed an inverse expression of miR-148A and -133A with the HLA-G protein in situ and in vitro . Stable miR overexpression caused a downregulation of HLA-G protein enhancing the NK and LAK cell-mediated cytotoxicity in in vitro CD107a activation assays revealing a HLA-G-dependent cytotoxic activity of immune effector cells. A significant higher frequency of CD3 + /CD8 + T cell lymphocytes, but no differences in the activation markers CD69, CD25 or in the presence of CD56 + , FoxP3 + and CD4 + immune cells were detected in HLA-G + compared to HLA-G - RCC lesions. This could be associated with higher WHO grade, but not with a disease-specific survival. These data suggest a miR-mediated control of HLA-G expression in RCC, which is associated with a distinct pattern of immune cell infiltration. |
