Impairment of natural killer cell and dendritic cell functions by the soluble form of MHC class I-related chain A in advanced human hepatocellular carcinomas

Abstract

MHC class I-related chain A (MICA), a human ligand of natural killer (NK) cell stimulatory receptor NKG2D, is expressed in human hepatocellular carcinomas (HCC). Earlier research demonstrated that the soluble form of MICA (sMICA) is released from some types of tumors, but its presence and role in HCC was not determined. Serum sMICA was studied in 26 patients with HCC. In vitro experiments were performed to examine the impact of sMICA on NK cell expression of NKG2D and subsequent dendritic cell (DC) activation. The levels of sMICA were frequently elevated in patients with advanced HCC. The elevation of sMICA was associated with down-regulated NKG2D expression and impaired activation of NK cells. In vitro experiments revealed that sMICA derived from advanced HCC was responsible for down-modulation of NKG2D expression and NK cell functions. NK cells upon stimulation of human hepatoma cells induced maturation of DC and enhanced the allostimulatory capacity of DC; maturation and activation of DC were completely abolished when NK cells were pre-treated with sMICA-containing serum. sMICA is present in sera of patients with advanced HCC and may serve as a tumor evasion mechanism by negatively modulating both innate and adaptive immunity.