Natural killer group 2D-major histocompatibility complex class I polypeptide-related sequence A activation enhances natural killer cell-mediated immunity against hepatocellular carcinoma: A review

The recent clinical introduction of immune checkpoint inhibitors has improved therapeutic outcomes in patients with advanced hepatocellular carcinoma. However, these therapies targeting CD8⁺ T lymphocytes have a response rate of approximately 30%. In addition to CD8⁺ T lymphocytes, natural killer (NK) cells represent promising therapeutic targets for hepatocellular carcinoma, because they comprise 30%–50% of all lymphocytes in the liver and contribute to antitumor immunity. A recent meta-analysis revealed that the percentage of infiltrating NK cells in hepatocellular carcinoma correlates with a better patient outcome. Similarly, our previous genome-wide association study on chronic viral hepatitis showed that a single-nucleotide polymorphism of major histocompatibility complex class I polypeptide-related sequence A (MICA), a ligand to the NK activating receptor, plays a critical role in hepatocarcinogenesis. In this review, we summarize the mechanisms underlying the regulation of MICA and NK group 2D expression in chronic hepatitis. Furthermore, we describe recent reports on MICA single-nucleotide polymorphism-driven hepatocarcinogenesis. The suppression of MICA shedding could represent a promising approach for immunosurveillance, as increased expression of membrane-bound MICA achieved through the use of a MICA shedding inhibitor also enhances NK cell-mediated cytotoxicity.