Expression and shedding of MHC class I-related chain (MIC) A and B molecules in human carcinoma cell lines

Chitadze, Guranda

The interaction of the MHC class 1-related chain molecules (MIC) A and B with the corresponding Natural Killer Group 2D receptor elicits cytotoxicity of Natural Killer cells and T cell subsets. Albeit absent in normal tissue, these molecules are constitutively expressed on transformed cells and play an important role in tumor immunosurveillance. Consequently, the ectodomain shedding of MICA and MICB is regarded as an important mechanism of the immune escape of cancer cells. However, the proteolytic machinery responsible for the shedding of endogenous MICA/MICB from tumors has not been well defined. In this study, we analyzed different human tumor entities including mammary, pancreatic and prostate carcinomas for the expression and shedding of endogenous MICA and MICB molecules. Flow cytometry and ELISA revealed that all the tested cells constitutively expressed MICA and MICB on the cell surface and also released NKG2D ligands into the supernatant. Inhibitor studies showed that metalloproteases are responsible for both the constitutive and phorbolester-induced generation of soluble MICA/B, whereas aspartate, cysteine and serine proteases are not involved in this process. Consequently, the inhibition of metalloproteases reduced the level of released MICA/B and increased cell surface expression. In the prostate carcinoma cell line PC-3, MICA was not shed at all, despite expression of these molecules on the cell surface. Genotyping of this cell line showed that the reason for this discrepancy was the expression of the truncated allelic variant, MICA*008:01, indicating an allele-specific regulation of this process. Studies employing RNA interference not only revealed a prominent role of a disintegrin and metalloprotease (ADAM) 10 and 17 in the shedding of NKG2D ligands but also a differential susceptibility of MICA to the proteolytic activity of ADAM10/17. Altogether, inhibition of shedding responsible proteases lowers the release of tumor-promoting soluble MICA/B and increases the cell surface density of these molecules and in that way presumably also the immunogenic potential of tumors. The detailed analysis of the proteolytic machinery responsible for the shedding of NKG2D ligands such as MICA/B from tumor cells might open the field for new strategies in tumor therapy.

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Chitadze, Guranda: Expression and shedding of MHC class I-related chain (MIC) A and B molecules in human carcinoma cell lines. 2013.

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