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

Tumor cells have been shown recently to escape immune recognition by developing resistance to Fas-mediated apoptosis and acquiring expression of Fas ligand (FasL) molecule that they may use for eliminating activated Fas+ lymphocytes. In this study, we report that tumor-specific T lymphocytes isolated from tumor lesions by repeated in vitro TCR stimulation with relevant Ags (mostly represented by normal self proteins, such as MART-1/Melan A and gp100) can develop strategies for overcoming these escape mechanisms. Melanoma cells (and normal melanocytes) express heterogeneous levels of Fas molecule, but they result homogeneously resistant to Fas-induced apoptosis. However, CD4+ and CD8+ CTL clones kill melanoma cells through Fas/FasL-independent, granule-dependent lytic pathway. In these lymphocytes, Ag/MHC complex interaction with TCR does not lead to functional involvement of FasL, triggered, on the contrary, by T cell activation with nonspecific stimuli such as PMA/ionomycin. Additionally, melanoma cells express significant levels of FasL (detectable on the cell surface only after treatment with metalloprotease inhibitors), although to a lesser extent than professional immune cells such as Thl clones. Nevertheless, antimelanoma CTL clones resist apoptosis mediated by FasL either in soluble form or expressed by Thl lymphocytes or FasL+ melanoma cells. These results demonstrate that CD4+ and CD8+ antimelanoma T cell clones can be protected against Fas-dependent apoptosis, and thus be useful reagents of immunotherapeutic strategies aimed to potentiate tumor-specific T cell responses.
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PMID:Human melanoma-reactive CD4+ and CD8+ CTL clones resist Fas ligand-induced apoptosis and use Fas/Fas ligand-independent mechanisms for tumor killing. 968 82

Lymphocytes from patients with melanoma have been used to clone melanoma associated antigens which are, for the most part, nonmutated melanocyte tissue differentiation antigens. To establish a mouse model for the use of these 'self' antigens as targets for anti-tumor immune responses, we have employed the mouse homologues of the human melanoma antigens Tyrosinase, Tyrosinase Related Protein-1 (TRP-1), gp100, and MART-1. We sought to generate antisera against these proteins for use in the construction of experimental recombinant and synthetic anti-cancer vaccines, and for use in biologic studies. Using genes cloned from the B16 mouse melanoma or from murine melanocytes, we immunized rabbits with plasmid DNAs coated onto microscopic gold beads that were then delivered using a hand-held, helium-driven 'gene gun'. This strategy enabled us to generate polyclonal rabbit sera containing antibodies that specifically recognized each antigen, as measured by immunostaining of vaccinia virus infected cells. The sera that we generated specifically for TRP-1, gp100, and MART-1 recognized extracts of the spontaneous murine melanoma, B16. The identities of the recognized proteins was confirmed by Western blot analysis. The titers and specificities of these antisera were determined using ELISA. Interestingly, serum samples generated against murine MART-1 and gp100 developed antibodies that were cross-reactive with the corresponding human homologues. Recognition of human gp100 and murine Tyrosinase appeared to be dependent upon conformational epitopes since specificity was lost upon denaturation of the antigens. These antisera may be useful in the detection, purification and characterization of the mouse homologues of recently cloned human tumor associated antigens and may enable the establishment of an animal model of the immune consequences of vaccination against 'self antigens.
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PMID:Generation of polyclonal rabbit antisera to mouse melanoma associated antigens using gene gun immunization. 969 58

The antibody to the melanoma antigen recognized by T cells (anti-MART-1, clone M2-7C10) is a newly described antibody to a transmembrane protein previously detected only in normal skin melanocytes, retinal tissue, and malignant melanoma (MM). This antibody is the basis for ongoing immunotherapy protocols at the National Institutes of Health/National Cancer Institute. HMB-45, an antibody directed against a premelanosome glycoprotein, although used predominantly for the diagnosis of MM, has shown consistent staining in angiomyolipoma (AML), lymphangiomyoma/lymphangiomyomatosis (LAM), and clear cell sugar tumor (CCST), a group of tumors proposed to be related on the basis of their common perivascular epithelioid cells, which exhibit various degrees of smooth muscle differentiation, melanogenesis, and intracytoplasmic membrane bound granules. To compare the immunoreactive patterns of anti-MART-1 with those of HMB-45, we performed avidin-biotin immunoperoxidase testing on nonmelanocytic neoplasms (AMLs, LAMs, CCSTs) known to express HMB-45. Microwave pretreatment was necessary for anti-MART-1 staining on paraffin-embedded material. Our results showed that all of the 10 cases of AML were immunoreactive for both anti-MART-1 and HMB-45; that all of the 4 cases of LAM were positive for HMB-45, with 1 of the 4 reacting with anti-MART-1; and that 3 of the 4 cases of CCST expressed HMB-45, whereas 1 of the 4 was positive for anti-MART-1. Our findings lent additional support to previous studies that proposed a relationship between AML, LAM, and CCST. Anti-MART-1 and HMB-45 share similar specificities for these nonmelanocytic tumors, but the former seems to be a less sensitive marker for these lesions. In similar circumstances, anti-MART-1 and HMB-45 are potentially useful clinical markers.
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PMID:Comparison of melanoma antigen recognized by T cells (MART-1) to HMB-45: additional evidence to support a common lineage for angiomyolipoma, lymphangiomyomatosis, and clear cell sugar tumor. 972 Apr 95

The authors retrospectively tested the potential value of paraffin-reactive monoclonal antibodies (A103 against melan-A, T311 against tyrosinase) and antibody KBA62 as immunohistochemical markers for amelanotic metastatic melanomas. The study cases included 72 amelanotic metastases of known cutaneous melanomas, 59 poorly differentiated carcinomas, 73 sarcomas of varying histogenesis, 4 Leydig cell tumors, 10 high-grade lymphomas, and 6 plasmoblastic/anaplastic myelomas. The results were compared with immunostainings for S-100 protein and HMB-45. HMB-45, antimelan-A, and antityrosinase showed almost identical staining results, with a sensitivity of 0.85 for HMB-45 and of 0.86 for both antimelan-A and for antityrosinase. HMB-45 and antityrosinase both had a specificity of 1.00; the specificity of antimelan-A was 0.95 as a result of a positive reaction in three of three adrenocortical carcinomas and four of four Leydig cell tumors. KBA62 stainings resulted in a sensitivity of 0.86 for melanomas. A positive immunoreactivity of KBA62 alone had a specificity of only 0.83, but in conjunction with anti-S-100 protein (sensitivity, 1.00; specificity, 0.87) and anticytokeratin 8/18/19 (CK), a KBA62+/S-100+/CK- immunophenotype identified all except one of the melanoma cases that were negative for the three melanocyte-specific markers with a specificity of 0.99. In conclusion, we found comparable immunohistochemical sensitivities of HMB-45, antityrosinase, and antimelan-A for a highly specific identification of approximately 85% of amelanotic metastatic melanomas on paraffin sections. Melanomas that were negative for all of these specific markers might be sensitively and specifically detected with anti-S-100 protein and KBA62.
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PMID:Tyrosinase, melan-A, and KBA62 as markers for the immunohistochemical identification of metastatic amelanotic melanomas on paraffin sections. 972 May 2

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

Several tumor antigens have been described as candidates for immunotherapy. Our study compared HLA-A2-restricted epitopes from 5 antigens commonly expressed by melanomas, i.e., Melan-A/MART-1 peptides (26-35 and 27-35), tyrosinase (368-376), gp-100 (280-288), MAGE-3 (271-279) and NA17-A (1-10), for their relative capacity to promote the development of cytotoxic and cytokine-producing specific CD8+ lymphocytes within melanoma-invaded lymph nodes. We used short-term cultured melanoma-invaded lymph node lymphocytes (MILLs) and tested responses developed by these cells to peptide-pulsed TAP-deficient T2 cells. We measured both the lytic response developed by MILLs and the fraction of these cells that secreted interferon-gamma (IFN-gamma), as deduced from intracellular cytokine labeling. Reverse transcription-polymerase chain reaction (RT-PCR) was used to analyze the expression of the 5 antigens within melanoma-invaded lymph nodes. Melan-A/MART-1, tyrosinase and gp-100 peptides were recognized by MILLs derived, respectively, from 8 of 20, 5 of 19 and 4 of 20 melanoma-invaded lymph nodes expressing these antigens. Most MILLs specific for Melan-A/MART-1 and tyrosinase exhibited both lysis and IFN-gamma responses, whereas most of those specific for gp-100 developed only lysis. Weak lysis without IFN-gamma secretion was developed against NA17-A and MAGE-3 peptides by MILLs from, respectively, 3 of 9 and 2 of 14 lymph nodes expressing these antigens. Our data show a prevalence of both cytotoxic and IFN-gamma-secreting effector T cells specific for differentiation antigens within HLA-A2 melanoma-invaded lymph nodes, which makes these antigens attractive targets for specific immunotherapy.
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PMID:Frequency and relative fraction of tumor antigen-specific T cells among lymphocytes from melanoma-invaded lymph nodes. 975 54

Monoclonal antibody (MAb) A103 specifically detects Melan A/MART-1 protein expression. Melan A/MART-1-derived peptides are recognized by CD8+ T-cells and are used in immunotherapy. We examined formalin-fixed paraffin-embedded tissue from 57 melanomas (34 primary, 23 metastatic) and 39 control cases (junctional, dermal, compound, Spitz, Reed and balloon-cell naevi) using the alkaline phosphatase and anti-alkaline phosphatase immunochemical method after antigen retrieval. Immunoreactivity was rated as low, medium or high, and staining pattern as homogeneous or heterogeneous. Staining with MAb A103 showed a sensitivity of 88% for melanoma, with a very high specificity for melanocytic cells. Immunopositivity decreased along with clinical stage, with stage I showing 100%, stage II 88%, stage III 90% and stage IV 75% immunoreactivity. Staining changed from an exclusively homogeneous pattern in the early clinical stages to a more heterogeneous pattern in the later stages. Melanocytic control tissues consisting of naevi of different subtypes all showed weak to moderate homogeneous immunoreactivity, with polarity towards the epidermis. Analysis of short-term melanoma cell cultures using reverse transcription-polymerase chain reaction (RT-PCR) enzyme-linked immunosorbent assay (ELISA) demonstrated mRNA expression in only one third of the originally immunopositive tumours, suggesting rapid mRNA expression loss in culture. MAb A103 allows the detection of melanoma-associated Melan A/MART-1 protein expression in routine archival tissue and thus enables the profiling of melanomas suited for immunotherapy approaches involving Melan A/MART-1 derived epitopes.
Melanoma Res 1998 Aug
PMID:Melan A/MART-1 immunoreactivity in formalin-fixed paraffin-embedded primary and metastatic melanoma: frequency and distribution. 976 9

In this work, we addressed the possibility to enhance the "in vitro" generation of CTLs recognizing tumor-associated antigens (TAAs) by using an inactivated recombinant vaccinia virus encoding B7.1 and B7.2 costimulatory molecules (rVV-B7.1/2). Antigen presenting cells (APCs) infected by rVV-B7.1/2 and pulsed with MART-1/Melan-A27-35 HLA-A2.1-restricted peptide induced significantly higher specific cytotoxic activity than peptide-loaded APCs infected by wild-type VV, both in VV-sensitized and naive donors. When APCs were infected with a rVV encoding both MART-1/Melan-A27-35 and B7-1/2 (rVV-B7.1/2-M), a significantly more effective CTL generation was observed as compared with cultures stimulated by APCs infected with a rVV encoding the TAA epitope only (rVV-M). These enhancing effects were detectable irrespective of a previous VV-specific sensitization. Most importantly, fibroblasts, devoid of antigen-presenting capacity upon peptide pulsing or infection with rVV-M, could be turned into effective APCs after infection by rVV encoding TAA epitopes and costimulatory molecules. In these experiments, by using separate recombinant viral constructs, we observed a predominant role of B7-1 as compared with B7-2 in the induction of TAA-specific CTLs. Taken together, our data indicate that replication-incompetent rVV encoding TAA epitopes and costimulatory molecules are able to induce highly effective generation of tumor-specific CTLs. Therefore, these vectors could represent valuable clinical tools for immunotherapy of melanoma patients.
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PMID:Enhanced generation of cytotoxic T lymphocytes using recombinant vaccinia virus expressing human tumor-associated antigens and B7 costimulatory molecules. 978 2

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

Several antigens, including the products encoded by the genes MAGE-1 and MAGE-3, are recognized on human melanoma cells by HLA-A1, HLA-A2, or HLA-Cw*1601*-restricted T cells on autologous or HLA-matched melanoma cell lines. T-cell recognition of naturally processed MHC class I-presented peptides, or alternatively synthetic peptides derived from MAGE-1 or MAGE-3, leads to cytokine release as well as to a cytotoxic T-cell response in these antimelanoma-directed polyclonal or clonal effector T-cell populations. Recent reports suggest that the activity of T lymphocytes infiltrating melanoma in vivo appears to be impaired. We report here the characterization of the in vitro (in the presence of 6000 IU interleukin 2) expanded tumor-infiltrating lymphocyte (TIL) T-cell line PM2-B2 derived from a patient with rapidly progressing and therapy-resistant head and neck melanoma. The TIL cell line PM2-B2 did not lyse, but instead released granulocyte-macrophage colony-stimulating factor in response to the autologous tumor or HLA-A1-matched allogeneic tumor cell lines. The TIL line PM2-B2 did not kill the MHC class I natural killer/lymphokine-activated killer target cell lines Daudi or K562. The fine specificity of the TIL line PM2-B2 restricted by HLA-A1 was further characterized by evaluating specific granulocyte-macrophage colony-stimulating factor release in response to MHC class I-eluted peptides derived from HLA-A1(+) melanoma cell lines. TIL PM2-B2 failed to recognize the recently described HLA-A1-presented peptides derived from the gene products encoded by MAGE-1 or MAGE-3. PCR-based analysis of the freshly harvested tumor from patient PM2-B2 revealed the presence of message for the melanoma-associated gene products MAGE-1 and MAGE-3, but not for tyrosinase or MART-1/MELAN-A. Acid elution and high performance liquid chromatography fractionation of MHC class I-presented peptides from HLA-A1-matched melanoma cell lines 397 or 888 revealed that TIL PM2-B2 recognized at least three distinct peptide epitopes eluting in high performance liquid chromatographic bioactive fractions 5/6, 36, and 51/52. These bioactive peaks appeared to be shared among HLA-A1(+) melanoma cell lines. We suggest, based on this report, that HLA-A1-presented melanoma-derived peptides (other than those previously reported peptides derived from MAGE-1 or MAGE-3) may represent targets for TIL recognition as defined by cytokine release, but not cytotoxicity. Such an immune response differentially defined by cytokine release, but absent cytotoxic functions, may either reflect the impaired cytolytic function of the TIL population or reflect the inherent nature of HLA-A1-presented melanoma T-cell epitopes leading to cytokine release, but not to a cytotoxic T-cell response. Additionally, this report suggests that the individual T-cell immune response to melanoma may be rather complex, involving diverse T-cell effector functions (e.g., cytotoxicity or cytokine release), each of which should be evaluated in studies of antitumor-specific T-cell reactivity.
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PMID:Detection of naturally processed and HLA-A1-presented melanoma T-cell epitopes defined by CD8(+) T-cells' release of granulocyte-macrophage colony-stimulating factor but not by cytolysis. 981 95


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