UMLS:C0025202 - FACTA Search

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Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the last 7 years significant progress has been made in the identification of melanoma-associated antigens recognized by cytotoxic T lymphocytes (CTL). These antigens belong to three main groups: cancer/testis-specific antigens (MAGE, BAGE, GAGE, PRAME and NY-ESO-1), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2), and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). In this review we have summarized the available data concerning the characterization of melanoma-associated antigens, focusing on their immunogenic and protective properties. The development of a strong immune response to differentiation antigens is limited by the existence of tolerance to these "self"-antigens, permitting the involvement of only T cells with low affinity T-cell receptors. Among the melanoma differentiation antigens, only gp100 has been shown to be a tumor regression antigen. The cancer/testis-specific antigens such as MAGE and PRAME should potentially be highly immunogenic antigens. They contain several potential HLA class I binding epitopes and are present only in the testes, which are not accessible to the cells of the immune system owing to the lack of direct contact with the immune cells and the lack of HLA class I expression on the surface of germ cells. But only two patients have been found who responded to these antigens in vivo, indicating their genuinely low immunogenicity. A comparison of the predicted secondary structures of these two groups of antigens (cancer/testis-specific and differentiation antigens) revealed enrichment of long alpha-helical stretches in the cancer/testis-specific antigens. We hypothesize that such highly organized stable structures could, first, reduce denaturation of the protein and, thus, ubiquitinylation as a degradation signal, and, second, diminish the efficiency of the protein unfolding - a necessary step in the proteolytic cleavage by proteasomes. High structural stability could therefore be responsible for the low immunogenicity of these proteins. In this case, modifications decreasing the stability of these proteins might be a means of improving the immune response to these potentially therapeutically useful antigens.
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PMID:Melanoma-associated antigens recognized by cytotoxic T lymphocytes. 974 May 4

We report here the identification of a new shared human melanoma antigen recognized by a human leukocyte antigen (HLA)-A*68011-restricted cytotoxic T lymphocyte clone (CTL 128). The cDNA encoding this antigen is composed of a partially spliced form of the melanocyte differentiation antigen tyrosinase-related protein (TRP)-2, containing exons 1-4 with retention of intron 2 and part of intron 4 (TRP-2-INT2). The sequence coding for the antigenic epitope is located at the 5' end of intron 2 and is available for translation in the same open reading frame of the fully spliced TRP-2 mRNA. This peptide is also recognized by CTL 128 when presented by the HLA-A*3301, a member of the HLA-A3-like supertype that includes the HLA-A*68011. Quantitative reverse transcription PCR analysis carried out on total and/or cytoplasmic mRNA demonstrated that, in contrast to the fully spliced TRP-2 mRNA expressed in melanomas, normal skin melanocytes, and retina, the TRP-2-INT2 mRNA could be detected at significant levels in melanomas but not in normal cells of the melanocytic lineage. Instead, in these normal samples, both the spliced and the unspliced transcript of gp100 were expressed at high levels. Absence of endogenous TRP-2-INT2 expression in melanocytes was also confirmed by lack of recognition of HLA-A*68011-transduced, TRP-2(+) melanocyte lines by CTL 128. These results indicate that a partially spliced form of a differentiation antigen mRNA, present in the cytoplasmic compartment of neoplastic but not normal cells of the melanocytic lineage, can be the source of a melanoma-restricted T cell epitope.
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PMID:Translation of a retained intron in tyrosinase-related protein (TRP) 2 mRNA generates a new cytotoxic T lymphocyte (CTL)-defined and shared human melanoma antigen not expressed in normal cells of the melanocytic lineage. 974 19

In a search for potentially tumour-specific MHC-class-II-restricted antigens, the immunogenicity of endogenous peptides that had been eluted from HLA-DR molecules of the human melanoma cell line FM3 (HLA-DRB1*02x, DRB1*0401) was tested in vitro. Two 16-mers representing gp100 positions 44-59, and annexin II positions 208-223 bound well to isolated DRB1*0401 molecules and are discussed here. HLA-DR-matched normal donors' T cells were cultured with peptide-pulsed artificial antigen-presenting cells (CHO cells cotransfected with genes for HLA-DRB1*0401 and CD80 and coexpressing high levels of both human molecules). Specific sensitization was achieved against both peptides, as measured in assays of autocrine proliferation and interleukin-2 secretion. Moreover, responses to native autologous melanoma cells but not to autologous B cells were also observed. In view of the expression of fas by the activated T cells and of fas ligand by the melanoma cells, blockade of potential fas/ fas-ligand interactions was undertaken using monoclonal antibodies (mAb). The antagonistic fas-specific mAb M3, but not the fas agonist M33, caused a markedly enhanced T cell response to FM3 cells. These results demonstrate that synthetic peptide antigens are able to sensitize T cells in vitro for effective MHC-class-II-restricted recognition of melanoma cells.
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PMID:Tumour-specific MHC-class-II-restricted responses after in vitro sensitization to synthetic peptides corresponding to gp100 and Annexin II eluted from melanoma cells. 975 76

Many melanoma epitopes are presented to cytotoxic T-lymphocytes (CTLs) by major histocompatibility complex (MHC) class I molecules, and it is reasonable to expect that the epitopes would be good substrates for the transporter associated with antigen processing (TAP), as TAP plays a major role in the transport of peptides into the endoplasmic reticulum (ER) for binding to MHC class I molecules. However, we have previously shown that several melanoma-associated epitopes, such as those derived from tyrosinase, gp100, MAGE-1 and MAGE-2 antigens, are in fact poor substrates for TAP. During the process of determining why these epitopes were capable of eliciting a strong CTL response, yet were poor substrates for TAP, it was observed that the epitopes possessed amino acids at their N-terminus that were deleterious for TAP binding as described for the peptide-binding motif for human TAP. We therefore postulated that the epitopes were transported by TAP as longer precursor molecules, and then trimmed in the ER to the appropriate size for presentation to T-cells. In an effort to test this hypothesis we synthesized a set of peptides, derived from the tyrosinase (YMNGTMSQV) and MAGE-1 (EADPTGHSY) epitopes, which possess N-terminal extensions of up to four amino acids. We show here that the longer peptides are indeed transported into the ER at a significantly higher level than the original epitopes. The data indicate that the longer melanoma-associated peptides are the preferred substrates for TAP, and further support the notion that peptides can be trimmed at the N-terminus in the ER during antigen processing.
Melanoma Res 1998 Aug
PMID:TAP prefers to transport melanoma antigenic peptides which are longer than the optimal T-cell epitope: evidence for further processing in the endoplasmic reticulum. 976 10

Melanogenesis-related proteins play important roles in melanin synthesis and antigenicity of melanomas. Identification of highly expressed melanoma-associated antigens (MAA) that are immunogenic in humans will provide potential targets for cancer vaccines. Melanogenesis-related proteins have been shown to be MAA. Autoantibody responses to these MAA have been shown to react with melanoma cells and melanocytes, and suggested to play a role in controlling melanoma progression. To assess antibody responses to potential melanoma/melanocyte autoantigens, the open-reading frame sequences of tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, and melanoma-associated glycoprotein antigen family (gp100/pmel17) genes were cloned and expressed as recombinant proteins in E. coli. Purified recombinant antigens were employed to detect antibodies in sera of melanoma patients and normal healthy donors. By affinity enzyme-linked immunosorbent assay and western blotting, all recombinant antigens were shown to be antigenic. The main subclass of antibody response to these antigens was IgG. Most importantly this study demonstrated anti-TRP-2 and anti-gp100/pmel17 IgG responses in melanoma patients. Only one of 23 normal donors had an antibody response to the antigens tested. MAA-specific IgG antibodies in sera were assessed in melanoma patients (n = 23) pre- and post-polyvalent melanoma cell vaccine treatment. Polyvalent melanoma cell vaccine treatment enhanced anti-MAA antibody responses; however, only anti-TRP-2 and anti-gp100/pmel17 antibody response was enhanced. These studies suggest that four melanogenesis-related proteins are autoimmunogenic and can be used as potential targets for active-specific immunotherapy.
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PMID:Antibody responses to melanoma/melanocyte autoantigens in melanoma patients. 976 50

Peptide vaccination against tumor Ags can induce powerful systemic CTL responses. However, in the majority of patients, no tumor regression is noted. To study this discrepancy, we analyzed CTL reactivity in a melanoma patient (F001) vaccinated with g209-2M peptide, a single residue variant of gp100(209-217). G209/g209-2M-reactive CTL were identified in post- but not prevaccination PBL. Limiting dilution analysis identified one predominant CTL clone (C1-35), with TCR Vbeta6s2, recognizing g209/HLA-A*0201-expressing targets. Additionally, two autologous melanoma lines (F001TU-3 and -4) and 20 separate tumor-infiltrating lymphocyte cultures were generated from a fine needle aspirate of a metastatic lesion progressing after initial response to vaccination. Both F001TU did not express gp100 and were not recognized by C1-35. Loss of gp100 by F001TU correlated with a marked reduction of gp100 expression in the same metastatic lesion compared with prevaccination. Thus, ineffectiveness of C1-35 and tumor progression could be best explained by loss of target Ag expression. Interestingly, 12 of 20 tumor-infiltrating lymphocyte cultures recognized F001TU, but none demonstrated g209/g209-2M reactivity, suggesting a functional dissociation between systemic and local immune response. This study suggests that vaccination effects must be analyzed in the target tissue, rather than in the systemic circulation alone.
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PMID:Functional dissociation between local and systemic immune response during anti-melanoma peptide vaccination. 978 Jan 92

The human melanocyte lineage-specific antigen gp100 contains several epitopes recognized by cytotoxic T lymphocytes (CTL). However, most of the epitopes reported to date are HLA-A2.1-restricted. Despite the high frequency of HLA-A2.1 in melanoma patients, effective population coverage requires the identification of epitopes restricted by other frequent HLA alleles. Herein, HLA-A3 binding, gp100-derived synthetic peptides were tested for their capacity to elicit anti-melanoma CTL in vitro using CD8+ T cells from healthy donors as responders and peptide-pulsed autologous dendritic cells as antigen-presenting cells. Of 7 peptides tested, 2 (gp100[9(87)] and gp100[10(86)]) induced CTLs that killed melanoma cell lines expressing HLA-A3 and gp100. Additional MHC-binding studies to various HLA molecules belonging to the HLA-A3 superfamily (HLA-A*1101, -A*3101, -A*3301 and -A*6801) were performed to determine whether these CTL epitopes could further increase potential population coverage. Further experiments indicated that the peptide gp100[9(87)], which bound to HLA-A11 with high affinity, was capable of inducing specific CTLs that killed melanoma cells expressing gp100 and HLA-A11 molecules. Our results indicate that the gp100[9(87)] peptide corresponds to a CTL epitope which may be restricted by either the HLA-A3 or HLA-A11 allele, emphasizing its utility for the design and development of epitope-based therapies for melanoma.
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PMID:Identification of gp100-derived, melanoma-specific cytotoxic T-lymphocyte epitopes restricted by HLA-A3 supertype molecules by primary in vitro immunization with peptide-pulsed dendritic cells. 979 43

During the last years significant progress has been achieved in the identification of melanoma-associated antigens (MAA) recognized by cytotoxic T lymphocytes (CTL). These antigens belong to three main groups: tumor-associated testis-specific antigens (MAGE, BAGE, GAGE and PRAME), melanocyte differentiation antigens (tyrosinase, Melan-A/MART-1, gp100, TRP-1 and TRP-2) and mutated or aberrantly expressed antigens (MUM-1, CDK4, beta-catenin, gp100-in4, p15 and N-acetylglucosaminyltransferase V). For the identification of these antigens, CTL cultures from mainly only 4 different melanoma patients have been used. These patients developed a strong anti-melanoma response resulting in long-lasting disease-free periods, pointing to the importance of the identification of highly immunogenic melanomas. In each of these patients, the immune response was observed against a unique set of 4 to 6 individual antigenic epitopes, on one hand suggesting the low immunogenicity of the individual antigens, and on the other pointing to the importance of the identification of additional highly immunogenic melanomas for the discovery of new MAA. The analysis of the available data on the immunogenic and protective properties of individual MAA confirms their low immunogenicity. In our study, we focused on the identification of especially highly immunogenic melanomas among a panel of 40 newly established melanoma cell lines. So far, only two such melanoma cell lines, FM3 and FM57 have been identified in this panel. The immunogenic properties of uncloned FM3 cells and several FM3 clones have been further investigated. It was found that the immunogenic properties of melanoma cells are mainly determined by the expression of progression-associated antigens as well as by ecto-ATPase, a molecule which is able to modulate cell adhesion. Cloning the cultures of PBL, stimulated with uncloned FM3 or with the highly immunogenic FM3 clone, FM3.29, has permitted us to identify the immune response against eight different MAA, five of these probably representing not previously described antigens. (Tab. 2, Fig. 2, Ref. 68.)
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PMID:The immunogenic properties of human melanomas and melanoma-associated antigens recognized by cytotoxic T lymphocytes. 981 Jul 66

Specific CD8(+) CTL recognition of melanoma requires expression of MHC class I molecules as well as melanoma-associated peptide epitopes. Human melanoma cells may escape immune recognition by a variety of means, including global or allelic down-regulation of MHC class I molecules. Stable MHC class I cell surface expression requires delivery of cytosolic peptides into the endoplasmic reticulum by the peptide transporter molecules TAP1 and TAP2, with peptides subsequently transported to the cell surface in complexes containing MHC class I heavy chain and beta2-microglobulin. We have evaluated a series of mechanisms resulting in MHC class I down-regulation in a human melanoma cell line, Mz18, typed as HLA-A2(+), A3(+), B7(+), B57(+), Cw1(+), and Cw6(+) by genomic PCR analysis. The melanoma cell line Mz18 exhibits a global down-regulation of MHC class I heavy chain transcripts; beta2-microglobulin; the proteasome subunits LMP2/7, involved in generating cytosolic peptide fragments; and the peptide transporter molecules TAP1 and TAP2, involved in peptide transport from the cytosol into the endoplasmic reticulum. IFN-gamma treatment of Mz18 melanoma cells leads to up-regulation of LMP2/7 and TAP1/2, as well as to up-regulation of HLA-B and HLA-C MHC loci alleles, but not HLA-A2 or HLA-A3. Karyotypic analysis and fluorescence in situ hybridization with chromosome 6 and MHC class I-specific probes showed complex rearrangement of one chromosome 6 involving the MHC class I locus on 6p and translocation of 6q to the long arm of chromosome 19. To evaluate the capability of melanoma Mz18 to present tumor-specific peptides to HLA-A2-restricted, melanoma-specific CTLs, we restored HLA-A2 surface expression by retroviral-mediated transfer of functional HLA-A2 cDNA. Melanoma peptides could only be presented and recognized by CTLs if the HLA-A2-transfected Mz18 cell line was first treated with IFN-gamma, thereby restoring LMP2/7 and TAP1/2 expression and function. Because several melanoma antigens recognized by T cells have been reported to be presented by HLA-A2 (MART-1/Melan-A, tyrosinase, gp100, and MAGE-3), the loss of HLA-A2 molecules may represent an important mechanism by which many melanomas evade immune recognition. These findings suggest that patients entering clinical trials for immunotherapy with melanoma vaccines should be carefully examined for tumor cell allelic MHC class I loss and whether such MHC class I antigen down-regulation can be restored by cytokines.
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PMID:Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. 981 14

An important element in melanoma vaccine construction is to identify peptides from melanoma-associated Ags that have immunogenic potential in humans and are recognized by CD8+ T cells in vivo. To identify such peptides, we evaluated HLA-A*02+ melanoma patients immunized to a polyvalent vaccine containing multiple Ags, including MAGE-3, Melan-A/MART-1, gp100, tyrosinase, melanocortin receptor (MC1R), and dopachrome tautomerase (TRP-2). Using a filter spot assay, we measured peripheral blood CD8+ T cell responses, before and after immunization, to a panel of 45 HLA-A*0201-restricted peptides derived from these Ags. The peptides were selected for immunogenic potential based on their strong binding affinity in vitro to HLA-A*0201. Vaccine treatment induced peptide-specific CD8+ T cell responses to 22 (47.8%) of the peptides. The most striking finding was the HLA-independent heterogeneity of responses to both peptides and Ags. All responding patients reacted to different combination of peptides and Ags even though the responding patients were all A*0201+ and the peptides were all A*0201-restricted. From 9 to 27% of patients developed a CD8+ T cell response to at least one peptide from each Ag, but no more than 3 (14%) reacted to the same peptide from the same Ag. This heterogeneity of responses to individual peptides and Ags in patients with the same haplotype points to the need to construct vaccines of multiple peptides or Ags to maximize the proportion of responding patients.
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PMID:HLA-independent heterogeneity of CD8+ T cell responses to MAGE-3, Melan-A/MART-1, gp100, tyrosinase, MC1R, and TRP-2 in vaccine-treated melanoma patients. 986 32

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