NK cell activating ligands on human malignant cells: Molecular and functional defects and potential clinical relevance

Malignant transformation of cells is frequently associated with HLA class I antigen downregulation or loss. This abnormality provides malignant cells with a mechanism to escape control by HLA class I antigen-restricted, tumor antigen-specific cytotoxic T lymphocytes. Surprisingly, HLA class I antigen downregulation or loss by tumor cells is not associated with control of tumor growth by natural killer (NK) cells, as it would be predicted by the “missing-self” hypothesis. Here, we discuss the role of NK cell activating ligand abnormalities as well as HLA class I molecule and ICAM-1 shedding in the lack of control of tumor growth by NK cells with emphasis on their molecular mechanisms. In addition, we discuss the impact of these abnormalities on cancer immune surveillance.