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)

Melanoma is a cancer where the immune system is believed to play an important role in the control of malignant cell growth. To study the variability of the immune response in melanoma patients, we derived melanoma cell lines from several HLA-A2+ and HLA-A2- patients. The melanoma cell lines studied were designated FM3, FM6, FM9, FM28, FM37, FM45, FM55p, FM55M1 and FM55M2 and were established from eight metastatic tumors as well as from one primary tumor from a total of seven different patients. On the basis of the ability of tumor cells to induce specific cytotoxic T lymphocytes (CTL) from peripheral blood lymphocytes (PBL) in mixed lymphocyte/tumor culture with HLA-A2+ melanoma cells, the FM3 cell line was characterized as highly immunogenic. To investigate the expression of different melanoma-associated antigens recognized by CTL on different melanoma cell lines, we selected the cell line FM3 for restimulation and further T cell cloning experiments. The lytic activity of CTL clones with good proliferative activity was examined using a panel of HLA-A2+ and HLA-A2- melanoma cell lines. None of the tested HLA-A2- melanoma cell lines were susceptible to lysis by the CTL clones, whereas allogeneic HLA-A2+ melanoma cell lines were lysed only by a few CTL clones. On the basis of their reactivity with different melanoma cell lines, it was possible to divide the present CTL clones into at least four groups suggesting the recognition of at least four different antigens. Three of these target structures probably are different from already-described HLA-A2-restricted melanoma-associated antigens, because their expression in the different melanoma cell lines do not correlate with the recognition of melanoma cells by these CTL. The results first indicate that poorly immunogenic melanoma cells may express melanoma-associated antigens, and also suggest that, by using CTL clones obtained against different HLA-class-I-matched melanoma cells, it is possible to define such antigens.
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PMID:Generation of human-melanoma-specific T lymphocyte clones defining novel cytolytic targets with panels of newly established melanoma cell lines. 765 72

HLA-A2.1-associated peptides were extracted from human melanoma cell lines and used to study epitopes for melanoma-specific HLA-A2.1-restricted CTL. CTL were generated from tumor-involved nodes by in vitro stimulation, initially with autologous melanoma cells and subsequently with allogeneic A2.1+ melanoma cells. These CTL lysed autologous melanoma plus four allogeneic HLA-A2.1+ melanomas, including an HLA-A2.1-transfected melanoma. K562, HLA-A2- melanomas and HLA-A2+ nonmelanomas were not lysed. HLA-A2.1 molecules were purified from human melanoma cell lines by immunoaffinity column chromatography of detergent-solubilized cell pellets. Peptides bound to the MHC molecules were acid eluted and fractionated by reversed phase HPLC. Individual fractions were assessed for their ability to reconstitute melanoma-specific epitopes by addition to the HLA-A2.1+ Ag-processing mutant, 721.174XCEM.T2 (T2). Five peaks of reconstitution were observed. Second dimension HPLC separations of reconstituting fractions revealed evidence for two distinct reconstituting peptides within one of these peaks. Based on these data, a minimum of six distinct peptides associated with HLA-A2.1 and recognized by melanoma-specific CTL are present on these different melanoma lines. These data document the presence of multiple peptide-defined CTL epitopes that are shared by at least three unrelated human melanoma cell lines.
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PMID:Recognition of human melanoma cells by HLA-A2.1-restricted cytotoxic T lymphocytes is mediated by at least six shared peptide epitopes. 768 Oct 84

Immunoperoxidase staining of frozen sections from surgically removed melanoma lesions showed that anti-human leukocyte antigen (HLA)-A2, A28 monoclonal antibody (mAb) stained keratinocytes, but did not stain melanoma cells in 21% of the 14 primary and 44% of the 9 metastatic lesions tested. The loss of HLA-A2 and/or A28 allospecificities did not affect the staining patterns with mAb recognizing monomorphic determinants of HLA Class I antigens, in terms of percentage of stained melanoma cells and intensity of staining. This finding is not likely to reflect the sensitivity of the immunoperoxidase technique, since cytofluorographic analysis detected no significant difference in the staining pattern by mAb to monomorphic determinants of HLA Class I antigens between a melanoma cell line and an autologous transfectant that had acquired HLA-A2 antigens following gene transfer. The results of the present study imply that the frequency of abnormalities in HLA Class I antigen expression by melanoma cells is higher than that described in the literature, since selective losses of HLA Class I allospecificities are not detected by staining of melanoma cells with mAb to monomorphic determinants of HLA Class I antigens. The latter reagents have been used in most of the published studies to characterize the expression of HLA Class I antigens in melanoma lesions. Furthermore, the present results provide a mechanism for the unexpected resistance to cytotoxic T-cell-mediated lysis and the unexpected poor clinical course of the disease in some patients despite a high expression of HLA Class I antigens as measured by staining of melanoma cells with mAb to monomorphic determinants.
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PMID:Selective loss of human leukocyte class I allospecificities and staining of melanoma cells by monoclonal antibodies recognizing monomorphic determinants of class I human leukocyte antigens. 768 17

We have pursued our analysis of potential tumor-rejection antigens recognized on human melanoma by autologous cytolytic T lymphocytes (CTL). We reported previously that 3 distinct antigens (A,B,C) were recognized on melanoma cell line SK29-MEL in association with HLA-A2. Selection for melanoma-cell variants resistant to anti-A CTL revealed that antigen A consists of at least 2 determinants (Aa, Ab) which can be lost separately. Genetic linkage between Aa and Ab was suggested by concomitant loss of Aa and Ab in an immunoselected tumor-cell variant. This variant was also resistant to an autologous CTL clone restricted by HLA-B45, indicating that this CTL may also recognize a determinant of antigen A. Of 11 allogeneic HLA-A2 melanoma cell lines that were tested, 5 expressed both Aa and Ab, 1 expressed only Aa, and 1 only Ab. None of them was lysed by anti-B or anti-C CTL clones. A CTL clone derived from another HLA-A2-melanoma patient was found to have exactly the same lytic pattern as the anti-Ab CTL of the first patient. This suggested that it may be possible to elicit an anti-Ab response in many HLA-A2 patients. We conclude that there are at least 2 distinct antigens presented in association with HLA-A2 that are common to many melanomas and therefore constitute promising targets for specific immunotherapy.
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PMID:Analysis of antigens recognized on human melanoma cells by A2-restricted cytolytic T lymphocytes (CTL). 769 Mar 46

Using a newly described pH 3.3 acid elution technique, peptides were extracted by denaturation of class I molecules on the surface of human melanomas. HPLC fractionation of this material revealed six T cell epitopes (termed P1-P6) recognized by HLA-A2-restricted, melanoma-specific tumor infiltrating lymphocyte (TIL) lines. Three of these fractions (P1, P2, and P4) appeared to represent shared/immunodominant melanoma Ag recognized in the context of HLA-A2 because they were expressed by 4/4 HLA-A2+ melanoma cell lines and were each recognized by all four oligoclonal HLA-A2-restricted TIL lines examined. Interestingly, P1 and P2 (but not P3-P6) could also be recognized by these same TIL when presented by the HLA-Aw69 class I molecule, which is closely related to HLA-A2. P3, P5, and P6 displayed more restricted expression and were differentially recognized by the four oligoclonal TIL lines. These results suggest that synthetic peptide derived from P1, P2, and P4 sequences (when deduced) may form the basis of effective prophylactic or therapeutic melanoma vaccines by stimulating CD8+ CTL in HLA-A2+ individuals. This approach of identifying T cell epitopes presented by class I molecules should prove generally applicable to the study of other tumors recognized by class I-restricted CTL.
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PMID:Identification of human melanoma peptides recognized by class I restricted tumor infiltrating T lymphocytes. 769 Aug 11

T cell lines generated by primary in vitro stimulation with B7-expressing HLA-A2+ melanoma cells lyse HLA-A2+ melanomas, but not non-melanomas that are HLA-A2+. Other data have demonstrated lack of response of these T cell lines against non-HLA-A2 melanomas. These concepts are verified by data from MALME MEL, which is killed, and MALME FIB, which is not. In no case was lysis directed at targets expressing potential allo-antigens (except for HLA-A2+ melanomas). A19 and Aw33 have not been excluded as possible allo-targets (but no data suggests they are). In total, it appears that much of the lytic activity observed in the two T cell lines is directed against HLA-A2-restricted, melanoma-specific antigens.
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PMID:A phase I trial of B7-transfected or parental lethally irradiated allogeneic melanoma cell lines to induce cell-mediated immunity against tumor-associated antigen presented by HLA-A2 or HLA-A1 in patients with stage IV melanoma. NCI protocol T93-0161. BRMP protocol 9401. 770 89

Four of ten HLA-A2-restricted melanoma specific CTL that were derived from tumor-infiltrating lymphocytes (TIL) and administered to patients recognized the gp100 melanoma Ag and nine of ten recognized the MART-1 Ag. Adoptive transfer of the four gp100-reactive CTL, but not the other TIL, resulted in tumor regression when infused into autologous patients along with IL-2. Tumor regression was thus correlated with the recognition of gp100 by the administered T cells (p = 0.0048). To identify the epitopes recognized by these four gp100-reactive CTL, 169 peptides containing HLA-A2.1 binding motifs were synthesized and screened for their recognition by TIL using cytotoxicity and IFN-gamma release assays. Five gp100 epitopes (two for TIL620, three for TIL660, one for TIL1143, and two for TIL1200) were recognized by CTL derived from different patients. Five of eight HLA-A2 binding melanoma epitopes (five gp100, one MART-1/Melan-A, two tyrosinase) had intermediate binding affinity to HLA-A2.1. These gp100 epitopes may be responsible for mediating tumor rejection in vivo and thus may be useful for the development of immunotherapies for patients with melanoma.
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PMID:Recognition of multiple epitopes in the human melanoma antigen gp100 by tumor-infiltrating T lymphocytes associated with in vivo tumor regression. 770 34

To determine whether T-cell-receptor (TCR) usage by T cells recognizing a defined human tumor antigen in the context of the same HLA molecule is conserved, we analyzed the TCR diversity of autologous HLA-A2-restricted cytotoxic T-lymphocyte (CTL) clones derived from five patients with metastatic melanoma and specific for the common melanoma antigen Melan-A/MART-1. These clones were first identified among HLA-A2-restricted anti-melanoma CTL clones by their ability to specifically release tumor necrosis factor in response to HLA-A2.1+ COS-7 cells expressing this tumor antigen. A PCR with variable (V)-region gene subfamily-specific primers was performed on cDNA from each clone followed by DNA sequencing. TCRAV2S1 was the predominant alpha-chain V region, being transcribed in 6 out of 9 Melan-A/MART-1-specific CTL clones obtained from the five patients. beta-chain V-region usage was also restricted, with either TCRBV14 or TCRBV7 expressed by all but one clone. In addition, a conserved TCRAV2S1/TCRBV14 combination was expressed in four CTL clones from three patients. None of these V-region genes was found in a group of four HLA-A2-restricted CTL clones recognizing different antigens (e.g., tyrosinase) on the autologous tumor. TCR joining regions were heterogeneous, although conserved structural features were observed in the complementarity-determining region 3 sequences. These results indicate that a selective repertoire of TCR genes is used in anti-melanoma responses when the response is narrowed to major histocompatibility complex-restricted antigen-specific interactions.
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PMID:Cytotoxic T-lymphocyte clones from different patients display limited T-cell-receptor variable-region gene usage in HLA-A2-restricted recognition of the melanoma antigen Melan-A/MART-1. 777 68

Cytotoxic T-lymphocytes (CTLs) can be isolated from human melanoma biopsies that specifically lyse autologous melanoma in vitro and can be effective therapeutic agents for patients with advanced disease. Recent evidence indicates that HLA-A2-restricted, melanoma-specific tumor-infiltrating lymphocytes (TILs) recognize melanomas obtained from different HLA-A2+ patients, suggesting the presence of one or more common melanoma antigens. Furthermore, T-cell receptor (TCR) repertoire analysis by other groups of TILs from fresh melanoma biopsies suggests that there is limited TCR V gene usage in TILs. One serious limitation in analyzing the TCR repertoire in fresh tumors has been the inability to correlate TCR usage with immune function. Therefore, the TCR repertoire was determined in long-term TIL cultures that specifically lysed autologous melanoma in vitro and in many cases mediated in vivo regression of metastatic cancer in patients with advanced disease. The TCR repertoire in cultured melanoma-specific TILs was diverse, with each TIL containing an average of 9.5 +/- 5.7 of the 23 V alpha and 11.2 +/- 5.9 of the 23 V beta subfamilies. Despite the large diversity observed, several V alpha and V beta genes (V alpha 1, V alpha 2, V alpha 22, V beta 13, V beta 14, and V beta 18) are very commonly found in melanoma-specific TILs. No statistically significant associations were observed between the presence of a TCR V gene subfamily in TILs and clinical response, HLA haplotype, or age of the culture. Even though the results in this study suggest that certain TCR V gene segments may be involved in immune responses to human melanoma, we were unable to demonstrate functionally that a particular T-cell clonotype recognizes melanoma tumor-associated antigens. Only the analysis of melanoma-specific CTL clones can determine which clonotypes are important in lysis of human melanoma.
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PMID:T-cell receptor repertoire in tumor-infiltrating lymphocytes. Analysis of melanoma-specific long-term lines. 780 31

The human MAGE-3 gene is expressed in many tumors of several histological types but it is silent in normal tissues, with the exception of testis. Antigens encoded by MAGE-3 may, therefore, be useful targets for specific anti-tumor immunization of cancer patients. We reported previously that MAGE-3 codes for an antigenic peptide recognized on a melanoma cell line by autologous cytolytic T lymphocytes (CTL) restricted by HLA-A1. Here we report that the MAGE-3 gene also codes for another antigenic peptide that is recognized by CTL restricted by HLA-A2. MAGE-3 peptides bearing consensus anchor residues for HLA-A2 were synthesized and tested for binding. T lymphocytes from normal individuals were stimulated with autologous irradiated lymphoblasts pulsed with each of three peptides that showed strong binding to HLA-A2. Peptide FLWGPRALV was able to induce CTL. We obtained CTL clones that recognized not only HLA-A2 cells pulsed with this peptide but also HLA-A2 tumor cell lines expressing the MAGE-3 gene. The proportion of melanoma tumors expressing this antigen should be approximately 32% in Caucasian populations, since 49% of individuals carry the HLA-A2 allele and 65% of melanomas express MAGE-3.
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PMID:A peptide encoded by human gene MAGE-3 and presented by HLA-A2 induces cytolytic T lymphocytes that recognize tumor cells expressing MAGE-3. 780 31


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