Major histocompatibility complex class I chain-related A and B molecules and their potential role in virus-associated cancers

Core Tip

Core Tip: Several oncogenic viruses have evolved multi-layered strategies to subvert the natural killer group 2-member D (NKG2D)-major histocompatibility complex class I chain-related genes A (MICA)/B axis and promote cancer progression. Human papillomavirus drives immune evasion through exosomal release of the truncated MICA*008 variant, which potently downregulates NKG2D and impairs natural killer (NK) cell cytotoxicity. Chronic hepatitis B virus and hepatitis C virus infections create a hypoxic/inflammatory tumor milieu that induces metalloproteases, generating soluble MICA/B that suppresses NKG2D on NK and CD8+ T cells. EBV evades NKG2D-mediated immunity through miR-bamHI-A rightward transcript 7-mediated repression of the transforming growth factor beta 1/cellular myelocytomatosis oncogene/MICA axis and latent membrane protein 2A-driven disruption of stress-induced ligand expression, reinforced by UPR-protein disulfide isomerase inhibition of proper MICA/MICB folding and trafficking. Kaposi’s sarcoma-associated herpesvirus exploits its E3 ubiquitin ligases K3 and K5 to ubiquitinate MICA and other NK-activating ligands such as activation-induced C-type lectin, triggering their endocytic removal and intracellular sequestration to disable multiple NK cell recognition pathways. Therapeutic strategies targeting this axis show considerable promise.