HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance

Changes in classical and nonclassical HLA class I as well as HLA class II antigens have been identified in malignant lesions. These changes, which are described in this review are believed to play a major role in the clinical course of the disease since both HLA class I and class II antigens are critical to the interaction between tumor cells and components of both innate and adaptive immune system. Abnormalities in HLA antigen expression in malignant cells, which range in frequency from 0–90%, are caused by distinct mechanisms. They include defects in β2-microglobulin (β2m) synthesis, loss of the gene(s) encoding HLA antigen heavy chain(s), mutations, which inhibit HLA antigen heavy chain transcription or translation, defects in the regulatory mechanisms, which control HLA antigen expression and/or abnormalities in one or more of the antigen processing, machinery (APM) components. More recently, epigenetic events associated with tumor development and progression have been found to underlie changes in HLA antigen, APM component, costimulatory molecule and tumor antigen (TA) expression in malignant cells. The types of epigenetic modifications that may occur in normal and malignant cells as well as their role in changes in HLA antigen expression by malignant cells have been reviewed. The epigenetic events associated with alterations in HLA antigen expression may be clinically relevant as, in some cases, they have been shown to impair the recognition of tumor cells by components of the adaptive immune system. The functional relevance and potential clinical significance of these epigenetic alterations have been addressed. Finally, unlike genetic alterations, epigenetic modifications can, in some cases, be reversed with pharmacologic agents that induce DNA hypomethylation or inhibit histone deacetylation. Therefore, strategies to overcome epigenetic modifications underlying changes in HLA antigen expression in malignant cells have been discussed.