MAGE-A in triple-negative breast cancer: molecular biology, epigenetic targeting, and immunotherapy

The MAGE-A family consists of proteins with restricted expression profiles in normal tissues but expressed in multiple solid tumor types including triple-negative breast cancer (TNBC). In this review, we describe and discuss the potential of MAGE-A family members as therapeutic targets in TNBC. Preclinical studies have shown that MAGE-A is more frequently expressed in TNBC compared with other breast cancer subtypes. MAGE-A protein expression induces epithelial-mesenchymal transition, invasive and metastatic capabilities of TNBC cells via AMPK degradation and p53 downregulation. MAGE-A expression is primarily regulated epigenetically through DNA methylation, histone modifications, and aberrant expression of non-coding RNAs. In terms of therapy, multi-epitope peptide-based vaccines against MAGE-A antigens have demonstrated efficacy in preclinical studies by promoting cytotoxic T cell-mediated killing of TNBC cells. Extensive preclinical evidence has led to multiple ongoing early-phase clinical trials to investigate the safety and efficacy of MAGE-A immunotherapies in TNBC patients. Novel therapeutic strategies targeting MAGE-A include multi-epitope MAGE-A peptide vaccines to mitigate heterogeneous MAGE-A expression and MHC restrictions in peptide-HLA matching. Future clinical trials evaluating MAGE-A peptide vaccines, and in combination with epigenetic drugs such as hypomethylating agents that re-express MAGE-A, hold potential to improve clinical outcomes for TNBC patients.