The Melanoma-Associated Antigen Family A (MAGE-A): A Promising Target for Cancer Immunotherapy?

SIMPLE SUMMARY: Given that selecting an appropriate target is the first step in developing effective cancer immunotherapy, we focus on melanoma-associated antigens (MAGEs), which are a subclass of cancer/testis (CT) antigens characterized by restricted expression in immune-privileged tissues and a variety of cancers. For a long time, possessing this combination of characteristics has made MAGEs a remarkable candidate for effective treatment. Based on promising clinical data from combinatorial therapies, ongoing clinical trials targeting MAGE-A antigens, as well as a thorough understanding of the crosstalk between cancer and immune control, a new era in cancer immunotherapy is expected. The goal of this review is to provide an in-depth understanding of the various strategies for targeting the MAGE-A family for cancer treatment, as well as to highlight some of the most exciting recent advances in this area. ABSTRACT: Early efforts to identify tumor-associated antigens over the last decade have provided unique cancer epitopes for targeted cancer therapy. MAGE-A proteins are a subclass of cancer/testis (CT) antigens that are presented on the cell surface by MHC class I molecules as an immune-privileged site. This is due to their restricted expression to germline cells and a wide range of cancers, where they are associated with resistance to chemotherapy, metastasis, and cancer cells with an increasing potential for survival. This makes them an appealing candidate target for designing an effective and specific immunotherapy, thereby suggesting that targeting oncogenic MAGE-As with cancer vaccination, adoptive T-cell transfer, or a combination of therapies would be promising. In this review, we summarize and discuss previous and ongoing (pre-)clinical studies that target these antigens, while bearing in mind the benefits and drawbacks of various therapeutic strategies, in order to speculate on future directions for MAGE-A-specific immunotherapies.