Stress-induced cancer antigens (MICA/B)

Stress-induced cancer antigens, primarily represented by MHC class I polypeptide-related sequence A (MICA) and B (MICB), are cell surface glycoproteins that are upregulated in response to cellular stressors such as DNA damage, oxidative stress, and malignant transformation (PMID: 29593025). These antigens are typically absent or expressed at very low levels on healthy cells but become highly prevalent on the surface of various solid and hematologic tumor cells (UniProt: Q29983). They function as ligands for the NKG2D activating receptor, which is expressed on natural killer (NK) cells and certain T cell subsets, thereby facilitating the immune-mediated destruction of cancerous cells (PMID: 12192402). However, many tumors employ a common evasion mechanism by proteolytically shedding these antigens from the cell surface using metalloproteinases, resulting in soluble forms (sMICA/B) that systemically inhibit NKG2D function and promote immune escape (PMID: 15852067). Therapeutic interventions, such as the monoclonal antibody CLN-619, are designed to bind these antigens and prevent their shedding, effectively "locking" them on the tumor surface to enhance immune recognition and stimulate antibody-dependent cellular cytotoxicity (ADCC) (Cullinan Oncology, 2023). By restoring the visibility of the tumor to the innate and adaptive immune systems, these therapies represent a novel approach to overcoming immune evasion in oncology.

Other names

NKG2D ligandsMHC class I polypeptide-related sequence A/BMICAMICBUL16-binding proteinsULBPStress-induced ligands

Prevention of proteolytic shedding of MICA/B from the tumor cell surface and enhancement of antibody-dependent cellular cytotoxicity (ADCC) to restore NKG2D-mediated immune surveillance.