Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the last few years, mutiple protein target antigens for immunorecognition by T cells have been identified on human melanoma. How melanoma lesions escape from functional antigen-specific immune recognition remains poorly understood. We have identified the concomitant loss of the immunodominant T cell-defined MART-1/Melan-A antigen and downregulation of the TAP-1 gene in a recurrent metastatic melanoma that was resected in 1993. This phenotype was not observed for an earlier autologous melanoma lesion resected in 1987. The "antigen loss" could be restored in the variant tumor cell line by simultaneously providing both the MART-1/Melan-A gene (by retroviral transfer) and the TAP-1 gene (by a bioballistic approach) resulting in tumor cell sensitivity to MART-1/Melan-A-specific cytotoxic T lymphocytes. This suggests that tumor escape from immune surveillance may have occurred in vivo as a sequential result of (a) antigen loss, and (b) downregulation of the peptide-transporter protein TAP-1 expression by this patient's tumor over a 6-yr period from 1987 to 1993. These results suggest that the characterization of the T cell response to melanoma in individual patients and definition of the immunologically relevant genetic defects in tumors may be required to select the most effective therapeutic strategies for a given patient.
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PMID:Tumor escape from immune recognition: lethal recurrent melanoma in a patient associated with downregulation of the peptide transporter protein TAP-1 and loss of expression of the immunodominant MART-1/Melan-A antigen. 883 13

MART-1 is expressed ir both normal and neoplastic cells of melanocytic origin. Peripheral blood mononuclear cells (PBMC) from melanoma patients recognize and lyse tumor cells after repetitive in vitro stimulation with the immunodominant peptide MART-1(27-35). In this study, we compared the characteristics of the cytotoxic T lymphocyte (CTL) response to MART-1 in PBMC from 13 HLA-A2 melanoma patients with PBMC from 9 normal healthy donors stimulated in vitro with MART-1(27-35) (AAGIGILTV) or FluM1(58-66) (GILGFVFTL) peptides. The expansion rate among CTLs from different patients was variable and did not correlate with the development of specificity against the MART-1(27-35) or FluM1(58-66) peptides. Specific anti-MART-1(27-35) cytotoxicity could be generated in 13 of 13 melanoma patients but only in 5 of 9 healthy donors (p < 0.001). Anti-FluM1(58-66) activity could be generated in six of seven melanoma patients and six of seven healthy donors. Specific activity against MART-1(27-35), but not FluM1(58-66), was detectable significantly earlier after repetitive in vitro stimulation in melanoma patients (22.7 +/- 2.0 days compared with 32.7 +/- 1.7 days for healthy donors, p < 0.01). This report provides the first evidence of an enhanced level of sensitization of tumor-bearing hosts compared with normal individuals against a differentiation antigen shared by tumor and normal cells of the same lineage. These findings may have important implications for delineating events involved in the biology of tumor rejection naturally or in response to active specific immunotherapy.
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PMID:Differential anti-MART-1/MelanA CTL activity in peripheral blood of HLA-A2 melanoma patients in comparison to healthy donors: evidence of in vivo priming by tumor cells. 887 21

The human MAGE-1, MAGE-3 and MART-1 genes code for antigens that are specifically recognized by cytolytic T lymphocytes in a MHC-restricted manner. The MAGE-1 and MAGE-3 genes are expressed in tumors of different histotypes but not in normal adult tissues (with the exception of testis), while the MART-1 gene appears to be selectively expressed in melanoma. MAGE-1, MAGE-3 and MART-1 antigens may therefore constitute useful targets for specific anti-tumor immunization of cancer patients. Here we have investigated the expression of MAGE-1, MAGE-3 and MART-1 in 11 neuroblastoma (NB) cell lines and 73 NB tumor masses. MAGE-1 and MAGE-3 transcripts were detected simultaneously in 36% of the cell lines and in 16% of tumor samples. The MAGE-1 gene was never expressed alone except in one tumor. In contrast, MAGE-3 mRNA was found in approximately 40% of the NB tumor samples in the absence of MAGE-1 mRNA. No expression of the MART-1 gene was observed in any cell line or tumor sample. No correlation was found between MAGE gene expression and clinical stage, event-free survival and presence or absence of N-myc amplification.
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PMID:Expression of MAGE-1, MAGE-3 and MART-1 genes in neuroblastoma. 890 Mar 75

Human melanoma antigens and their epitopes recognized by T cells have recently been identified. HLA-A2 binding epitopes of melanoma antigens MART-1 and gp 100 were characterized and suspected to be subdominant/cryptic self determinants. Together with other findings of tumor-specific mutated self peptides as tumor antigens recognized by T cells, the nature of the antitumor immune response to human melanoma has been revealed at a molecular level. These findings have implications not only for understanding of the immune response to self peptides in normal and pathologic conditions, but also for the development of immunotherapies for cancer and autoimmune diseases.
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PMID:T-cell recognition of self peptides as tumor rejection antigens. 890 75

CD8+ T lymphocytes recognize antigenic peptides presented by major histocompatibility complex (MHC) class I molecules. Individual peptide termini appear to be fixed at the C- and N-terminal ends. In contrast, central peptide side chains residues may point in different directions and exhibit limited flexibility, dependent on the MHC class I structural variation. For instance, position 97 in HLA-A201 has been shown to shift individual peptide species into different coordinations, one oriented towards the peptide N terminus, or more towards the C-terminal end. The conformational shape of such non-anchor peptide residues may affect the affinity of MHC/peptide/TCR interaction, resulting in quantitative, or qualitative different T cell effector functions. To characterize the impact of different amino acid residues occupying position 97 in HLA-A2 on peptide binding and presentation to CTL, we generated a panel of mutated HLA-A2 molecules containing either M, K, T, V, G, Q, W, P or H at position 97. The HLA-A0201 presented melanoma-associated MART-1/Melan-A derived peptide AAGIGILTV was employed to assess the impact of such position-97 mutations on HLA-A2 in peptide binding measured in an HLA-A2 reconstitution assay and presentation to AAGIGILTV-specific polyclonal or clonal T lymphocytes as measured by cytotoxicity, or interferon (IFN)-gamma and granulocyte/ macrophage colony-stimulating factor (GM-CSF) secretion. The high-affinity AAGIGILTV peptide bound to all position-97 mutants, albeit with differential efficiencies, and elicited specific release of IFN-gamma and GM-CSF by CTL. CTL responses were triggered only by the HLA-A2 wild type, by HLA-A2-H97 (histidine position 97 mutant), and HLA-A2-W97. The HLA-A2-M97 presenting molecule elicited enhanced cytokine release and CTL effector functions by polyclonal and by clonal effector T cells. These results indicate that MHC class I-bound peptides can trigger specific cytokine release by effector T cells independently of their ability to induce cytolysis. We conclude that relatively minor changes in the MHC class I peptide binding groove, including substitutions at position 97, can affect recognition by antigen-specific T cells. Mutant MHC class I molecules, such as those described here, may act as partial peptide antagonists and could be useful for inducing T lymphocytes with qualitatively different effector functions.
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PMID:Amino acid substitutions at position 97 in HLA-A2 segregate cytolysis from cytokine release in MART-1/Melan-A peptide AAGIGILTV-specific cytotoxic T lymphocytes. 892 47

Dendritic cells (DCs) are potent antigen-presenting cells that can activate quiescent T lymphocytes. When pulsed with tumor-associated antigen (TAA) peptide or protein, murine DCs can provide antitumor immunity. We reasoned that DCs retrovirally transduced with TAA genes might have important advantages over peptide- or protein-pulsed DCs, including long-term TAA presentation in vivo, and presentation of important but undefined epitopes. Therefore, we attempted to retrovirally transduce human DCs with a melanoma TAA gene (MART-1) and determine whether these transduced DCs could raise a specific antitumor response from quiescent autologous T lymphocytes. After retroviral transduction, human CD34+ cells were differentiated into DCs in vitro using granulocyte macrophage colony-stimulating factor, tumor necrosis factor alpha, and stem cell factor. This method consistently yielded a population of DCs as analyzed by morphology, phenotype, and MLR. Flow cytometric analysis revealed that 22-28% of cells expressing the DC phenotype also expressed a transduced marker gene. When DCs were transduced with the gene encoding MART-1, they stimulated much higher levels of cytokine release by MART-1-specific tumor-infiltrating lymphocytes than control DCs transduced with an irrelevant gene. In vitro stimulation using MART-1-transduced DCs but not control-transduced DCs raised specific antitumor CTLs from autologous quiescent T cells. These results provide evidence that human DCs can be retrovirally transduced with a TAA gene and that these transduced cells can raise a specific antitumor immune response in vitro. Transduced DCs may be useful for in vivo immunization against TAA.
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PMID:Retroviral transduction of human dendritic cells with a tumor-associated antigen gene. 897 Nov 74

Several epitopes in the human melanoma antigens recognized by HLA-A2-restricted CTLs have a relatively low MHC-binding affinity and as a result may be expressed at very low densities on the cell surface, indicating that these epitopes may not be efficient immunogens. To express these epitopes at higher densities on the surface of antigen-presenting cells and therefore improve their immunogenicity, a DNA construct in which a cDNA fragment encoding the melanoma epitope MART-1(27-35) or gp100(280-288) was inserted between sequences encoding the leader and the HLA-A*0201 protein. Cells transfected with these epitope-HLA fusion constructs were recognized by HLA-A2-restricted melanoma-reactive CTLs specific for the MART-1 or gp100 epitope. In addition, tumor-reactive CTLs could be induced from PBMCs of patients with metastatic melanoma by in vitro stimulation with HMY-C1R B-cell lines expressing the MART-1 or gp100 epitope-HLA-A*0201 fusion protein. These epitope-HLA fusion constructs may be useful for the development of immunotherapies for patients with melanoma.
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PMID:Induction of melanoma reactive T cells by stimulator cells expressing melanoma epitope-major histocompatibility complex class I fusion proteins. 900 May 54

Antigenic peptides derived from several differentiation antigens of the melanocyte lineage were recently identified in human melanomas as targets for HLA-A2.1-restricted cytotoxic T lymphocytes (CTLs). To examine their potential role in tumour-directed immune responses in vivo, we determined CTL reactivity against seven antigenic peptides derived from the Melan A/MART-1, tyrosinase and gp100/Pmel17 antigens in the peripheral blood of 10 HLA-A2+ healthy controls and 26 HLA-A2+ melanoma patients. The influenza matrix peptide (GILGFVFTL) presented by HLA-A2.1 was used as a control peptide. CTL reactivity was assessed in a mixed lymphocyte 'peptide' culture assay. Reactivity against Melan A/MART-1-derived peptide antigens was readily detectable in both melanoma patients and controls. Reactivity directed against tyrosinase-derived peptide antigens was also detected in both melanoma patients and healthy individuals, but less frequently. A measurable response against gp100/Pmel17-derived antigens was found in 1/10 controls and in 1/26 of the melanoma patients. Reactivity against the influenza matrix peptide was common in both melanoma patients and controls. Our findings show that precursor CTLs against melanocyte differentiation antigens can be detected in peripheral blood of melanoma patients and healthy individuals. The pattern of CTL reactivity directed against melanoma-associated antigens does not seem to be altered in melanoma patients. Despite antigen-specific CTL reactivity, tumour growth was not prevented in melanoma patients and autoimmune phenomena were not detected in healthy individuals. It remains to be determined whether precursor CTLs recognizing melanocyte differentiation antigens can be activated by immunization and lead to effective tumour rejection in vivo.
Melanoma Res 1996 Dec
PMID:Cytolytic T cell reactivity against melanoma-associated differentiation antigens in peripheral blood of melanoma patients and healthy individuals. 901 79

We reported previously that a large fraction of melanoma cell lines induced a suboptimal activation of specific CTL clones, characterized by good tumor cell lysis but no detectable IL-2 production. Using synthetic peptides, we demonstrated recently that this was due to expression of subthreshold levels of appropriate MHC-peptide complexes. We measure here by semiquantitative reverse transcription-PCR the expression of two melanoma Ag (NA17-A and Melan-A/MART-1) mRNAs in 13 melanoma cell lines and analyze the responses to these cell lines of specific HLA-A2-restricted CTL clones. In line with the idea that the density of MHC-antigenic peptide complexes on melanoma cells is a direct function of the Ag's mRNA level, we found that CTL lysis was grossly proportional to this level. We also established that a minimal level of transcription is required for melanoma cells to induce IL-2 secretion. Interestingly, all cell lines that expressed the Ag above this minimal level, either spontaneously or after gene transfection, stimulated the secretion by tumor-infiltrating lymphocyte of IL-2 amounts proportional to Ag expression unless they exhibited a defective expression of intracellular adhesion molecule-1 or LFA-3 molecules or a low expression of the restricting HLA element. These results indicate that optimal activation and therefore, doubtless, full functionality of melanoma-specific CTL clones critically depend on the mRNA level of the Ag in tumor cells and also on a minimal expression of the HLA restriction element, intracellular adhesion molecule-1, and LFA-3. These data provide a rationale for a better selection of patients to be included in Ag-specific immunization protocols.
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PMID:Optimal T cell activation by melanoma cells depends on a minimal level of antigen transcription. 901 65

A line of tumor-infiltrating lymphocytes (660TIL) specifically lysed the autologous HLA-A2+ melanoma (660MEL) and also most A2+ melanoma cell lines. We immunoprecipitated A2 from a large number (>10(12)) of 660MEL cells, extracted naturally processed peptides, fractionated them by HPLC, screened the fractions for recognition by 660TIL, and found a single predominant and a minor peak of activity. Although too little was recovered of the major 660MEL peptide to establish its sequence, HPLC fingerprinting showed that it did not correspond to any of the known A2-associated melanoma peptides recognized by T cells, including peptides from tyrosinase, MART-1/Melan-A, gp100 and MAGE-3. The major 660MEL antigenic peptide appears to be derived from MART-1/Melan-A but is neither AAGIGILTV nor ILTVILGVL nor any other MART-1/Melan-A peptide containing the A2 consensus motif. The multiplicity of melanoma peptides recognized by CD8+ T cells, most of which are non-mutated (including most likely the present 660MEL peptide), suggests the existence of unknown mechanisms, perhaps similar to those operating in autoimmune disorders, whereby T cells that recognize normal 'self' sequences become activated.
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PMID:Anti-melanoma cytotoxic T lymphocytes (CTL) recognize numerous antigenic peptides having 'self' sequences: autoimmune nature of the anti-melanoma CTL response. 904 14


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