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

Abstract

Infections with certain viruses are strong risk factors for specific cancers. The human major histocompatibility complex class I chain-related genes A (MICA) and B (MICB) are polymorphic, non-classical major histocompatibility complex class I genes located within the human leukocyte antigen region. Polymorphisms in these genes have been associated with susceptibility and outcomes of several virus-associated cancers. The underlying mechanisms involve modulation of natural killer cell- and CD8+ T cell-mediated cytotoxicity by disrupting the natural killer group 2-member D-MICA/B axis. The resulting soluble forms of both MICA and MICB have recently gained attention as potential predictive biomarkers for virus-induced malignancies and disease severity. Therapeutic strategies targeting this axis show considerable promise. This minireview summarizes the genetics and biology of MICA and MICB, highlighting their emerging importance in the pathogenesis of virus-associated cancers.

Keywords: Major histocompatibility complex class I chain-related genes A; Major histocompatibility complex class I chain-related genes B; Virus-associated cancers; Polymorphism; Natural killer group 2-member D; Natural killer-cell cytotoxicity

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.