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Our goal was to explore the association of melanoma-associated antigen-A (MAGE-A) gene expression with clinicopathological parameters and survival rates in patients with non-small-cell lung cancer (NSCLC) who had surgery. A systematic search of EMBASE, PubMed, Web of Science and The Cochrane Library databases was performed through 20 April 2019. The combined risk ratios (RRs) and hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) were calculated to assess the association of MAGE-A gene expression with clinicopathological characteristics and prognosis of patients with resected NSCLC, respectively. All statistical analyses were performed with Stata software, version 12.0. A total of 9 articles involving 1538 patients were included in our meta-analysis; most of the studies were from Asian countries. The results indicated that the expression of the MAGE-A gene was significantly correlated with lymph node metastases (RR 1.21, 95% CI 1.09–1.34; P = 0.001), high tumour-node-metastasis stage (RR 1.24, 95% CI 1.12–1.38; P

Summary To pursue an urgently needed treatment target for esophageal cancer (EC), we investigated the function of the recently discovered melanoma-associated antigen (MAGE)-D4 in squamous cell EC. MAGE-D4 messenger RNA (mRNA) expression was analyzed in nine EC cell lines using quantitative reverse transcription polymerase chain reaction. In 65 surgical specimens of squamous cell EC with no prior neoadjuvant therapy, MAGE-D4 mRNA expression in EC tissues and corresponding normal tissues was analyzed and compared, and evaluated in terms of clinicopathological factors. In representative cases, MAGE-D4 protein distribution was analyzed immunohistochemically. The heterogeneity of MAGE-D4 mRNA expression was confirmed in EC cell lines by quantitative reverse transcription polymerase chain reaction. In surgical specimens, MAGE-D4 mRNA expression was significantly higher in EC tissues than in corresponding normal tissues (P

Emerging evidence has pointed to biological roles of melanoma-associated antigens (MAGEs) in cancer development, progression and resistance to treatment. However, the mechanisms involved remain to be fully elucidated. In this report, we show that one of the MAGE proteins, MAGE-D2, suppresses the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 2 (TRAIL-R2) and plays an important role in protecting melanoma cells from apoptosis induced by TRAIL. MAGE-D2 was commonly expressed at increased levels in melanoma cells compared with melanocytes. Although its inhibition by small interfering RNA (siRNA) did not cause cell death, it rendered melanoma cells more sensitive to TRAIL-induced apoptosis. This was associated with enhanced formation of TRAIL death-inducing signaling complex and up-regulation of TRAIL-R2, and was blocked by a recombinant TRAIL-R2/Fc chimeric protein or siRNA knockdown of TRAIL-R2. Regulation of TRAIL-R2 by MAGE-D2 appeared to be mediated by p53, in that knockdown MAGE-D2 did not up-regulate TRAIL-R2 in p53-null or mutant p53 melanoma cells. In addition, inhibition of MAGE-D2 did not result in up-regulation of TRAIL-R2 in wild-type p53 cell lines with p53 inhibited by short hairpin RNA. Indeed, knockdown of MAGE-D2 led to up-regulation of p53 due to a transcriptional increase. The regulatory effect of MAGE-D2 on TRAIL-R2 expression and TRAIL-induced apoptosis was recapitulated in studies on fresh melanoma isolates. Taken together, these results identify the expression of MAGE-D2 as an important mechanism that inhibit TRAIL-induced apoptosis and suggest that targeting MAGE-D2 may be a useful strategy in improving the therapeutic efficacy of TRAIL in melanoma.

Background: The detection of circulating tumor cells (CTCs) in the peripheral blood of melanoma patients by quantitative real-time reverse-transcription PCR (qRT-PCR) analysis correlates with a poor prognosis. The assessment of CTCs from blood has been difficult because of lack of a good monoclonal antibody (mAb) directed against surface cell antigens to capture melanoma cells. Methods: Blood was collected prospectively from 57 melanoma patients (43 test and 14 test-development cases) and 5 healthy donors. High molecular weight melanoma-associated antigen (HMW-MAA)-specific mAbs bound to immunomagnetic beads were used to isolate CTCs. mRNA and/or DNA were extracted from CTCs. Testing for the expression of a melanoma-associated gene panel (MLANA, MAGEA3, and MITF) with qRT-PCR and for the presence of BRAFmt (a BRAF gene variant encoding the V600E mutant protein) verified the beads-isolated CTCs to be melanoma cells. A peptide nucleic acid-clamping PCR assay was used for BRAFmt analysis. Results: Spiking of peripheral blood cells (PBCs) with melanoma cells showed that the beads-based detection assay can detect approximately 1 melanoma cell in 5 × 106 PBCs. qRT-PCR analysis detected MLANA, MAGEA3, and MITF expression in 19 (44%), 29 (67%), and 19 (44%) of the patients, respectively. At least one biomarker of the panel was positive in 40 (93%) of the 43 melanoma patients. BRAFmt was detected in 17 (81%) of the 21 assessed stage IV melanoma patients. Conclusion: The assay of bead capture coupled with the PCR has utility for assessing CTCs in melanoma patients, which can then be characterized for both genomic and transcriptome expression.

Thus far, the use of classical anti-cancer treatment modalities had only rarely a beneficial impact on the prognosis of patients with metastatic melanoma. We as physicians have therefore the obligation as well as the chance to develop and test new therapeutic strategies. Our growing knowledge about the genetic basis of melanoma provides one platform to fulfil this task. Another one comes from our increasing understanding of the molecular and cellular mechanisms involved in the induction/modulation of immune responses, as well as the progress made in the field of identification of melanoma antigens, and allows for the development of a new generation of vaccines. The aim of this article is to discuss several of these new concepts towards the use of immune and gene therapy of melanoma.

Background: In the development of an antimelanoma vaccine, a critical factor is the identification of antigens that induce a strong immune response in humans and that are expressed by melanoma cells in vivo. The aim of this study was to identify candidate antigens for such vaccine. Methods: Sixtynine patients with surgically resected melanomas (American Joint Commission on Cancer [AJCC] stage III) were immunized with a polyvalent vaccine containing multiple melanoma antigens. Antimelanoma antibodies generated in the patients’ sera were used as probes to identify the melanoma antigens that are immunogenic in humans and that are expressed on the tumor tissue in vivo. Such responses were determined by an immunoblotting assay that employed an antigen source prepared from membrane fractions of freshly excised melanoma tissue. Results and Conclusions: Vaccine treatment stimulated antibody responses in 35 (51%; 95% confidence interval [CI] = 39%‐63%) of 69 sequentially enrolled patients. The antibodies were directed to one or more antigens with molecular masses of 45, 59, 68, 79, 89, 95, and/or 110 kd. The most immunogenic antigens were p110 and p68, which induced responses in 33% (95% CI = 22%‐44%) and 25% (95% CI = 15%‐35%) of patients, respectively. Both antigens were commonly expressed on different melanomas, but they were absent on autologous normal tissue and on an unrelated allogeneic tumor. All the above antigens are attractive candidates for vaccine construction. [J Natl Cancer Inst 1998;90

This review briefly discusses some recent developments in the use of monoclonal antibodies to study antigens of high molecular mass associated with melanomas, including information on their molecular profile, their heterogeneity, and the effect of interferon on their shedding by melanoma cells.

Immune reactivity to melanoma extracts was measured by the leukocyte adherence inhibition (LAI) test in 40 members of 3 melanoma-prone families. The melanoma patients had a wide range of responsiveness to the extract, the highest responder being a 10-year survivor. As a group, family members (including spouses) without disease had significantly elevated LAI responses compared to those of unrelated controls (P less than 0.01). Within the families, members with close exposure to melanoma patients for 10 years or more had a significantly higher response to melanoma antigen than did members with 0-5 years of close exposure (P less than 0.05). Responses of spouses and members at high risk of developing melanoma (B-K mole syndrome) also correlated with length of exposure to patients, which suggests that the elevated LAI response was not genetically determined. The high frequency of positive responses to melanoma antigens in these families, particularly in spouses, suggests the presence of transmissible melanoma-associated material capable of immunizing persons in contact with melanoma patients.

Quantities of a 100,000-mol wt human melanoma-associated antigen (MAA), defined by both monoclonal and polyclonal xenoantibodies, were measured in sera of 32 patients with malignant melanoma and 15 carefully documented healthy volunteers by use of an amplified sandwich enzyme-linked immunoabsorbent assay. Detectable levels of MAA were found in all normal adult sera. Five of 10 patients with stage III and 9 of 16 patients with stage IV disease had antigen levels that exceeded. the 95th percentile of serum levels in the normal donors (P less than .001). Elevated levels of the 100K MAA were associated with evidence of residual tumor (P less than .008): Only 3 of 13 patients with no evidence of tumor had abnormal values, whereas 9 of 16 patients with evident tumor had increased serum levels. Levels of the 100K MAA were unrelated to the levels of soluble immune complexes as detected by the fluid-phase C1q binding test. Molecular evaluation of the 100K MAA in serum indicated that the molecule associated with albumin in a strong, noncovalent manner. When the complex was dissociated by treatment with sodium dodecyl sulfate, the 100K MAA in serum comigrated with the molecule from spent culture medium of human melanoma cells. Antigen levels in sera were measured under these dissociating conditions. These studies suggest that measurement of the 100K MAA may be useful in monitoring tumor burden in patients with malignant melanoma.