Mapping MAGE-A4 expression in solid cancers for targeted therapies

Abstract

Melanoma-associated antigen A4 (MAGE-A4) is a promising target for anticancer therapy. However, limited contemporary data are available on the details of MAGE-A4 protein expression in different cancer types. In this study, the protein expression of MAGE-A4 is comprehensively studied in patients with unresectable and/or metastatic solid cancers to identify indications of the highest unmet medical need for anti-MAGE-A4 therapy. FFPE tumor sections from 200 patients, predominantly HLA-A*02:01 positive (n = 193), were examined using immunohistochemistry (IHC) to detect MAGE-A4 expression. The patient cohort comprised various cancer types to pinpoint differences in the prevalence and intensity of MAGE-A4 positivity. MAGE-A4 expression was observed in 35% (69 patients) of the overall cohort. Certain cancer types exhibited notably higher frequencies of MAGE-A4 positivity. Specifically, adenoid cystic carcinoma demonstrated the highest prevalence at 82%, followed by liposarcoma at 67%. Ovarian serous/high-grade carcinoma showed a 64% positivity rate, identical to that observed in squamous non-small cell lung cancer (NSCLC). Head and neck squamous cell carcinoma (HNSCC) presented a 60% prevalence, while esophageal cancer had a 54% prevalence of MAGE-A4 expression. These data highlight the variability of MAGE-A4 expression across different cancer types and underscore its relevance as a potential target of novel precision medicines. The significant presence of MAGE-A4 in specific cancers suggests potential for stratified therapeutic approaches and warrants further investigation into its role in oncogenesis and treatment response.

Keywords: biomarker; clinical trial; patient selection; target expression; translational analysis.

Figure 1

Abundance of MAGE-A4 expression. (a) Distribution of cyto/nuclear MAGE-A4 staining intensity by indication. Each bar represents one patient. (b) Example IHC image of a MAGE-A4-positive primary gastric adenocarcinoma biopsy with a cytoplasmic staining pattern, 65% positive tumor cells (60% at 1+ intensity), and H-score of 70. (c) Example IHC image of a MAGE-A4-positive primary squamous NSCLC biopsy with a mixed staining pattern, 70% positive tumor cells (40% at 1+ intensity; 25% at 2+ intensity), and H-score of 104. (d) Example IHC image of a MAGE-A4-positive lymph node metastatic biopsy of peritoneal cancer with a nuclear staining pattern, 95% positive tumor cells (92% at 3+ intensity), and H-score of 281. (b–d) Taken at ×20 original magnification; MAGE-A4 staining intensity was scored level 1+ (weak), 2+ (moderate), or 3+ (strong). HNSCC, head and neck squamous cell carcinoma; IHC, immunohistochemistry; H-score, histo-score; MAGE-A4, melanoma-associated antigen A4; NSCLC, non-small cell lung cancer.