MAGEA4

Detailed Information

Melanoma-associated antigen 4 (MAGE-A4, also known as MAGE-A or MAGE4) is a tumor/testis antigen belonging to the MAGE protein family. The MAGE-As subfamily is primarily located in the q28 region of the X chromosome, spanning approximately 45kb with three exons. The first two exons are quite short, while the third exon is longer. MAGE-A encodes a protein of 309-319 amino acids. Within cells, MAGE-A can be processed into antigenic peptides that bind to HLA class I molecules, forming complexes that are presented to CD8+ T cells via MHC class I molecules, inducing tumor-specific immune responses in cancer patients.

MAGE-A4 is exclusively expressed in normal testicular and placental tissues but is widely present in various cancer cells. The MAGE family was the first discovered cancer-testis antigen, inspiring research on specific immunity against tumor cells, with the MAGE-A subfamily being the most extensively studied. Research has shown that MAGE-A genes can activate specific T lymphocytes to attack tumor cells. Since more than half of tumors express MAGE genes, studying the MAGE-A family is significant for tumor immunology research.

MAGE-A4 Regulatory Mechanisms in Tumors

MAGE-A4 exhibits biological characteristics different from other family members, making it a preferred target antigen for tumor vaccines due to the following features:

1. It contains peptide segments that can bind to specific MHC molecules
2. The peptide-MHC complex formed with MAGE-A4 can bind to specific T cell receptors, promoting and activating specific T cells to kill tumor cells

Current research on MAGE-A4 is limited, and its regulatory mechanisms in tumors largely remain unknown. However, increasing evidence suggests that MAGE-A4 is involved in apoptosis and cell cycle processes.

Figure 1. Model illustrating the mechanism of MAGE-A4N1-induced apoptosis. (Sakurai T, et al., 2004)

Research has found that MAGE-A4 positively correlates with the tumor suppressor gene p53. Its C-terminal 107 amino acid fragment (MAGE-A4DeltaN1) can induce p53-dependent and p53-independent mechanisms through partial binding with Miz-1, enhancing p53's transcriptional activity while reducing p21 (Cip1) transcript and protein levels. The p53 gene is an important tumor suppressor that promotes cancer cell apoptosis and controls the cell cycle. Therefore, the biological activity of MAGE-A4 in inhibiting tumor progression suggests that this protein may protect the body from tumor attacks.

Other research suggests that the Twist1 enhancer binds indirectly to the MAGE-A4 promoter, causing MAGE-A4 amplification. However, additional studies indicate that MAGE-A4 can activate the Trans-lesion synthesis (TLS) pathway, inhibiting damage repair in normal cells while selectively activating DNA damage repair in chemotherapy-treated cells, leading to repair of tumor cell damage and resulting in tumor cell resistance to chemotherapeutic drugs.

MAGE-A4's Role in Various Tumors

Members of the MAGE-A family are expressed in various tumor tissues, including liver cancer, non-small cell lung cancer, bladder cancer, vulvar cancer, colorectal tumors, salivary gland tumors, and cervical cancer. Recent research has confirmed MAGE-A4 expression in multiple malignant tumors such as breast cancer, glioma, esophageal squamous carcinoma, prostate cancer, thyroid cancer, and oral squamous cell carcinoma. This widespread distribution suggests that MAGE-A4 may have important biological functions and clinical significance in various tumor types.

MAGE-A4 and Breast Cancer Research

Research has found that in triple-negative breast cancer (TNBC), the positivity rate of MAGE-A4 is 35.21%, higher than in non-triple-negative breast cancer. Additionally, studies indicate that MAGE-A4 expression is related to tumor clinical staging, with positive expression rates decreasing as clinical staging increases, suggesting it may play an inhibitory role in tumor progression. MAGE-A family members and NY-ESO-1 have been identified as tumor-associated antigens in breast cancer, positively correlating with estrogen receptor (ER) expression. At the same time, MAGE-As expression positively correlates with the poor prognostic indicator HER-2 in breast cancer. Furthermore, MAGE-A4 can activate CD4+ T cells in vivo, promoting immune responses that may kill tumor cells in early stages through immune reactions. These findings suggest that MAGE-A4 could be a potential target for TNBC.

MAGE-A4 and Glioma Research

Research has found statistically significant differences in MAGE-A4 expression in gliomas compared to normal brain tissue. The characteristic of MAGE-A4 not being expressed in normal somatic cells outside testicular tissue provides a theoretical basis for applying MAGE-A4 as a specific target antigen in glioma immunology research. MAGE-A4 mRNA expression is significantly higher in high-grade gliomas (grades III-IV) than in low-grade gliomas (grades I-II), suggesting that MAGE-A4 may be associated with malignant differentiation of gliomas and could serve as a reference indicator for assessing malignancy or for evaluating KPS scores and pathological grading in glioma patients. MAGE-A4 is specifically expressed in brain glioma tissues and significantly correlates with pathological grade, while showing no expression in normal brain tissue. Therefore, MAGE-A4 can be an ideal target for brain glioma immunology research.

MAGE-A4 and Esophageal Squamous Carcinoma Research

Using qPCR and immunohistochemistry methods, researchers found that in esophageal squamous carcinoma, the expression rate of MAGE-A4 reaches 50%, while expression levels are lower in atypical tissues and normal esophageal mucosa. This finding not only highlights the strict tumor expression specificity of the MAGE-A4 gene in esophageal squamous carcinoma but also confirms its potential role in the development of esophageal squamous carcinoma. Therefore, the MAGE-A4 gene can serve as a specific marker for esophageal squamous carcinoma, providing strong evidence for accurate clinical research.

MAGE-A4 and Other Tumor Research

Research shows that MAGE-A4 plays important roles in various tumors. For example, after silencing the MAGE-A4 gene expression in the lung squamous cancer cell line H1703 using small RNA, caspase-3 activity decreased by 58%. Another study on rectal cancer patients demonstrated the effectiveness of MAGE-A4 antigen peptide treatment, resulting in significantly reduced tumor growth rate and carcinoembryonic antigen levels. Additionally, a study of 187 non-small cell lung cancer patients showed that MAGE-A4 expression in tissues might lead to the loss of human leukocyte antigen HLA, resulting in significantly reduced 5-year survival rates. In esophageal cancer tissues, MAGE-4, MAGE-12, and NY-ESO-1 show varying degrees of expression, while they are not expressed in normal tissues adjacent to esophageal cancer. Furthermore, MAGE-A forms a molecular bridge with AR in prostate cancer, promoting AR transcriptional activity and subsequently promoting the growth of AR-dependent prostate cancer.

Clinical Research Prospects for MAGE-A4

Currently, 19 drugs targeting MAGE-A4 are in clinical research, with the most advanced being Afamitresgene Autoleucel, a TCR cell therapy that has entered phase III clinical trials for treating synovial sarcoma, esophageal cancer, and myxoid liposarcoma. Other drug types include bispecific antibodies, recombinant proteins, cell therapies, fusion proteins, and T-cell therapies. These drugs commonly target MAGE-A4, with some also targeting other targets such as CD3, MAGEA8, NY-ESO-1, PRAME, SSX2, survivin, WT1, HLA-A 24, CCL19, IL-7, and others.

The mechanisms of action for MAGE-A4-targeted drugs primarily involve regulating or inhibiting the expression or function of MAGE-A4 or other targets to induce tumor cell apoptosis or inhibit tumor growth and metastasis. Some drugs also function by enhancing immune system responses or replacing damaged cells. These drugs are primarily being researched for various types of tumors, such as melanoma, bladder cancer, non-small cell lung cancer, and head and neck tumors. Some drugs are also being investigated for other indications, such as hematological and lymphatic system diseases, digestive system diseases, and respiratory system diseases. The development of MAGE-A4-targeted drugs demonstrates their activity and diversity, highlighting the important position and prospects of this target in tumor immunology research.