Shedding of endogenous MHC class I‐related chain molecules A and B from different human tumor entities: Heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17

International Journal of Cancer - Tập 133 Số 7 - Trang 1557-1566 - 2013
Guranda Chitadze1, Marcus Lettau1, Jaydeep Bhat1, Daniela Wesch1, Alexander Steinle2, Daniel Fürst3, Joannis Mytilineos3, Holger Kalthoff4, Ottmar Janßen1, Hans‐Heinrich Oberg1, Dieter Kabelitz1
1Institute of Immunology Christian‐Albrechts‐University Kiel Kiel Germany
2Institute for Molecular Medicine, Goethe University Frankfurt am Main, Frankfurt am Main, Germany
3Institute of Clinical Transfusion Medicine and Immunogenetics, University of Ulm, Ulm, Germany
4Institute for Experimental Tumor Research, Molecular Oncology Division Christian‐Albrechts‐University Kiel Kiel Germany

Tóm tắt

The interaction of the MHC class I‐related chain molecules A and B (MICA and MICB) with the corresponding natural killer group 2, member D (NKG2D) receptor triggers cytotoxic effector activity of natural killer cells and certain T‐cell subsets and provides a costimulatory signal for cytokine production. Thus, the presence of MICA/B on transformed cells contributes to tumor immunosurveillance. Consequently, the proteolytic cleavage of MICA/B is regarded as an important immune escape mechanism of various cancer cells. To investigate the molecular machinery responsible for the shedding of endogenous MICA/B, we analyzed different human tumor entities including mammary, pancreatic and prostate carcinomas. Flow cytometry and enzyme‐linked immunosorbent assay (ELISA) revealed that all tested tumor cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. We demonstrate that the “a disintegrin and metalloproteases” (ADAMs) 10 and 17 are largely responsible for the generation of soluble MICA/B. Pharmacological inhibition of metalloproteases reduced the level of released MICA/B and increased cell surface expression. Studies using RNA interference not only revealed a prominent role of ADAM10 and ADAM17 in NKG2D ligand shedding but also a tumor cell‐specific role of ADAM10 and/or ADAM17 in shedding of MICA or MICB. Moreover, we report that in the prostate carcinoma cell line PC‐3, MICA was not shed at all but rather was secreted in exosomes. These data indicate that the release of NKG2D ligands from individual tumor entities is by far more complex than suggested in previously reported MICA/B transfection systems.

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International Journal of Cancer

Tập 133 Số 7

1557-1566

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