NKG2D ligands and Glioma-associated antigens (NKG2DL/GAA)

Glioma-associated antigens (GAAs) and NKG2D ligands (NKG2DLs) are a diverse group of cell-surface proteins that are overexpressed on malignant glioma cells, making them prime targets for immunotherapy. NKG2D ligands, including MICA, MICB, and the ULBP family (ULBP1-6), are stress-induced proteins that are typically absent on healthy tissues but upregulated during oncogenic transformation, serving as danger signals for the immune system (PubMed: 29038465). GAAs include specific markers such as IL-13Rα2, EGFRvIII, and HER2, which provide distinct molecular handles for therapeutic intervention (PubMed: 30635454). These targets are currently being utilized in the development of Chimeric Antigen Receptor (CAR) T-cell therapies, where T cells are engineered to recognize these antigens and initiate tumor cell lysis (PubMed: 31209229). For example, NKG2D-based CAR-T cells (e.g., CYAD-01) use the natural NKG2D receptor to target the multiple ligands expressed on the glioma surface (ClinicalTrials.gov: NCT04106167). While these targets offer a promising way to address the heterogeneity of glioblastoma, challenges such as antigen escape—where the tumor loses target expression—and the highly immunosuppressive tumor microenvironment remain significant barriers to clinical success. Additionally, potential on-target off-tumor toxicities must be carefully managed if these antigens are expressed at low levels in non-malignant tissues.

Other names

MICAMICBULBP1ULBP2ULBP3ULBP4ULBP5ULBP6IL-13Rα2EGFRvIIIHER2EphA2Tumor-associated antigens in glioma

Chimeric antigen receptor (CAR) T-cell mediated cytotoxicity targeting surface antigens and ligands, leading to T-cell activation and tumor cell lysis.