Melanoma-associated antigen 6 (MAGE-A6) peptide-HLA class I complex (MAGE-A6/HLA-I)

Melanoma-associated antigen 6 (MAGE-A6) is a cancer-testis antigen (CTA) that is normally expressed only in the testes and placenta but is frequently overexpressed in various solid tumors, including melanoma, lung, and bladder cancers (UniProt P43360; PMC4023743). As a member of the MAGE-A family, it plays a significant role in promoting tumor cell survival and proliferation by inhibiting the p53 tumor suppressor and facilitating the degradation of the energy sensor AMPK through the TRIM28 ubiquitin ligase complex (PubMed 20628142; PubMed 24813893). In cancer cells, MAGE-A6 is processed into short peptides that are presented on the cell surface by HLA class I molecules, such as HLA-A*01:01 or HLA-A*02:01 (PMC3662317; PMC6682510). This peptide-MHC complex serves as a specific target for engineered T-cell receptor (TCR) therapies, which aim to redirect the patient's immune system to recognize and destroy malignant cells (PMC6682510). Despite its potential as a therapeutic target, the high degree of homology between MAGE-A6 and other MAGE proteins, as well as potential cross-reactivity with unrelated proteins like Titin in the heart, has led to significant safety challenges in clinical trials (PubMed 23552927; PubMed 23552928). Consequently, precise patient selection based on HLA typing and MAGE-A6 expression levels is critical for the development of safe and effective MAGE-A6-targeted immunotherapies.

Other names

MAGE-6MAGEA6Melanoma-associated antigen 6Cancer/testis antigen 1.6CT1.6

T-cell receptor (TCR) mediated recognition of the peptide-MHC complex, leading to T-cell activation, cytokine release, and direct cytotoxic killing of the target cell.