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

We have investigated the relationship between in vitro cultivation of autologous melanoma metastases derived from different patients and their levels of expression of class-I and -II major histocompatibility complex (MHC) antigens and melanoma-associated antigens (MAAs). Cell cultures were established from 23 individual metastatic melanoma lesions from 10 patients and were tested early after isolation (between 3rd and 10th passages) for both constitutive expression and modulation by recombinant human leukocyte (IFN-alpha), fibroblast (IFN-beta) or immune (IFN-gamma) interferon of MHC antigens and MAA. All of the melanoma cell lines displayed altered antigen expression following IFN treatment. While in vitro cultures derived from different individuals varied in both constitutive and IFN-modified antigenic expression, cultures of autologous metastases derived from the same patient were very similar. In addition, differences in antigenic profile were apparent when early-passage in vitro cultures were compared with the same melanoma lesion, not established in culture, from which they were derived. The unique de novo and IFN-modified antigenic phenotype of cultures derived from different patients indicates that the antigenic phenotype displayed by melanoma cultures grown in vitro is genetically determined. The differences found between in vitro cultures and their corresponding in vivo lesions, as well as the antigenic heterogeneity displayed by multiple autologous melanoma lesions in vivo, suggest that the in vivo antigenic phenotype may be determined, at least in part, at an epigenetic level.
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PMID:Modulation of the antigenic phenotype of early-passage human melanoma cells derived from multiple autologous metastases by recombinant human leukocyte, fibroblast and immune interferon. 211 85

A CD8+ clone, identified by its T-cell receptor gamma- and beta-gene configuration, was shown to preferentially develop, in the bulk culture of melanoma tumor-infiltrating lymphocytes with recombinant interleukin 2 after 1 month. Thirteen CD8+ clones were obtained by limiting dilution culture of tumor-infiltrating lymphocytes from 43-days old culture. Four of these clones, analyzed for T-cell receptor rearrangements, exhibited exactly the same T-cell receptor gene pattern as tumor-infiltrating lymphocytes from the bulk culture, showing, therefore, that all the CD8+ clones were subclones. All the 13 CD8+ subclones were strongly cytotoxic for autologous melanoma cells but did not kill K562. A more complete cytotoxicity analysis showed that the clones did not kill autologous fibroblasts or Con A blasts or allogeneic tumor targets. Furthermore, specific killing was inhibited by monoclonal antibodies against CD3, CD8, T-cell receptors alpha beta, and class I major histocompatibility complex antigens indicating that effector-to-target cell recognition was mediated through the T-cell receptor in a major histocompatibility complex-restricted fashion. These data showed that human melanoma-specific cytotoxic T lymphocytes can be obtained from melanoma TIL and that a single cytotoxic T lymphocyte clone can be expanded to more than 10(10) cells without a loss of autotumor specificity.
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PMID:High proliferative capacity and specific antiautologous melanoma cytotoxicity of a human T-lymphocyte clone derived from tumor-infiltrating lymphocytes. 214 Oct 8

The experiments reported here describe the derivation of an immunogenic melanoma cell line from B16 melanoma by sequential in vitro mutagenization with two chemical mutagens: n-methyl n-nitro n-nitrosoguanine (MNNG) and ethane methyl sulfonate (EMS). Following in vivo screening of over 100 mutant melanoma clones, a single clone was selected for further study. When transplanted to the anterior segment of the mouse eye, the mutant melanoma (D5.1G4) underwent spontaneous resolution in 20% of the immunologically intact hosts. Tumor rejection involved extensive necrosis and culminated in phthisis of the tumor-containing eye. Histologic analysis revealed a prominent mononuclear cellular infiltrate in contrast to the parental progressor B16 melanoma. Immunologic analysis of tumor-bearing hosts showed variable cytotoxic T lymphocyte (CTL) responses but potent delayed-type hypersensitivity (DTH) responses directed against the melanoma cells. Fluorescent activated cell sorter (FACS) analysis of tumor-infiltrating cells from ocular tumors revealed a cellular response consisting mainly of CD8+ CTLs and macrophages. Cultured D5.1G4 melanoma cells demonstrated: 1) enhanced expression of class I major histocompatibility complex (MHC) antigens; 2) increased susceptibility to CTL-mediated killing; and 3) increased susceptibility to tumor necrosis factor (TNF)-mediated cytolysis. Therefore, the intraocular D5.1G4 mutant melanoma model provides important insights into the immunology and immunopathology of intraocular tumor rejection. More intensive analysis of this intraocular melanoma may yield strategies for directing the immune response toward tumor rejection while minimizing damage to normal ocular components.
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PMID:Immunologic evaluation of spontaneous regression of an intraocular murine melanoma. 215 14

Interactions between the cellular and humoral compartments of the human immune system are well documented. Leukoregulin (LR) is a hormone with the ability to upregulate the natural killer (NK) phenomenon by increasing target cell sensitivity to NK lymphocyte cytotoxicity. In the present report, the interactions between LR and human cytotoxic T-lymphocytes (CTLs) are described. Two cultured T-cell populations are specifically cytotoxic for autologous human melanoma and fail to lyse allogeneic melanoma, K562, or autologous peripheral blood lymphocytes (PBLs) in 4 h chromium release assays. Pretreating allogeneic melanoma or K562 with LR resulted in 19-67% lysis at an effector:target (E:T) ratio of 5:1, while no more than 10% lysis was observed without LR. Autologous PBLs were also subject to lysis when pretreated with LR (50% at an E:T of 40:1 with LR, and 2% without LR). The observed effect was dose-related and was most effectively inhibited by autologous cold targets, but persisted in the presence of antibody to human lymphocyte antigen class I antigens (w6/32). Lysis of autologous melanoma was not increased by pretreatment with LR. LR appears to mediate lysis of melanoma, NK targets, and normal PBLs by tumor specific CTLs. The effect is dose-related and non-major histocompatibility complex-restricted. The data do not support a significant role for LR in the normal physiology of human CTLs, but the striking effects in vitro may prove to be experimentally or therapeutically useful.
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PMID:Implications of leukoregulin to autologous tumor-specific human T-cell populations. 239 4

Autologous tumor-specific cytotoxic T-lymphocytes (CTLs), generated by repeated stimulation with autologous melanoma and expanded in interleukin 2, are major histocompatibility complex restricted. These CTLs recognize a common tumor-associated antigen in the presence of HLA class I determinants, suggesting that allogeneic melanomas which express the restricting HLA-A region antigen could substitute for the autologous tumor in the generation of CTLs. This was investigated in the HLA-A2 system. Four T-cell lines were established by stimulation of lymphocytes with either autologous tumor or an HLA-A2-matched allogeneic melanoma. Allogeneic stimulated CTLs specifically lysed the autologous tumor and demonstrated an identical pattern of HLA-A2 restriction, when compared to the autologous stimulated CTLs. Lysis by the allogeneic stimulated CTLs was blocked by a monoclonal antibody to HLA class I antigens; lysis was also inhibited by both autologous tumor or HLA-A2 allogeneic melanomas when evaluated in cold target competition studies. The allogeneic stimulated CTLs proliferated in response to both autologous tumor and HLA-A2 melanomas, but not in response to HLA-A2 nonmelanomas. By phenotypic analysis these CTLs were CD3+ and predominantly CD8+ cells. We conclude that autologous tumor-specific CTLs can be generated using HLA-A region-matched allogeneic melanomas for stimulation. Since established, HLA-typed melanoma tumor lines can be used in the absence of autologous tumor; this procedure can be applied clinically to a broad patient population and may prove useful in the adoptive immunotherapy of melanoma.
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PMID:Generation of human autologous melanoma-specific cytotoxic T-cells using HLA-A2-matched allogeneic melanomas. 240 72

Data concerning the in vitro lymphocyte response against autologous tumors are reviewed, with a particular emphasis on melanoma. Evidence for such an immune response to tumors has been accumulating over the last 10 years through the work of several groups of investigators. Proliferative and/or cytotoxic responses are detectable in approximately 70% of patients with primary tumors, whereas the in vitro reaction with metastatic lesions is much less frequent. This response is mainly mediated by T lymphocytes obtained from peripheral blood, tumor lesions, and lymph nodes, but patients' suppressor cells and factors have been reported to inhibit such response. Clonal analysis revealed a low but consistent frequency of antimelanoma-specific T-cytotoxic and/or proliferating cells even in metastatic melanoma patients; such effectors are major histocompatibility complex restricted and use the T-cell receptor for tumor recognition of unique and, possibly, cross-reacting melanoma-restricted antigens. The chemical and genetic nature of such molecules remains to be defined. After the limited but biologically fundamental clinical responses achieved by adoptive immunotherapy with interleukin-2 and lymphokine-activated killers, T cells appear to lend themselves as crucial new effectors in adoptive immunotherapy of human cancer and, in particular, of melanoma.
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PMID:Cellular immune response against autologous human malignant melanoma: are in vitro studies providing a framework for a more effective immunotherapy? 240 52

Treatment of the BL6 melanoma cells in vitro with N-methyl-N'-nitronitrosoguanidine dramatically increased their expression of H-2Kb and H-2Db antigens as well as beta 2-microglobulin but not Class 2 major histocompatibility complex antigens. The treated tumor cells also became immunogenic and were rejected in 70% of syngeneic C57BL/6 recipients, whereas these tumor cells produced progressively growing tumors in 100% of irradiated (550 R) or nude mice. In contrast to the effects of N-methyl-N'-nitronitrosoguanidine treatment, no influence of H-2 antigen expression or tumorigenicity was found when BL6 melanoma cells were treated with 5-azacytidine, phorbol myristate acetate, 5-bromodeoxyuridine, theophylline, or 6-thioguanine. H-2 antigen expression and the tumorigenic properties of 48 individual clones derived from BL6T2 melanoma line and 15 clones from the original BL6 melanoma were investigated. No H-2 antigens were found on the cell surface of the parental BL6 clones, whereas all tum- clones from the BL6T2 line expressed high levels of H-2 antigens. Although four of six tested tum+ clones had high levels of H-2b antigen expression similar to that of tum- clones, they were nonimmunogenic. These data indicate that an increase in major histocompatibility complex antigen expression is essential but not sufficient for the immunogenicity of tumor cells. This conclusion was also supported by the results of interferon treatment of BL6 melanoma cells: this induced an increase in the expression of beta 2-microglobulin and Class 1 H-2b antigens but not an increase in their immunogenicity. Detection of tumor-associated transplantation antigens on the melanoma cells also appeared to be dependent on the level of expression of H-2 antigens. Although tum+ clones grew in normal mice, immune mice were able to prevent the growth of tum+ clones with high levels of H-2 antigens. However, immune mice only partially inhibited the growth of the parental BL6 melanoma or tum+ clones which have low expression of H-2 antigens.
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PMID:Increase in H-2 antigen expression and immunogenicity of BL6 melanoma cells treated with N-methyl-N'-nitronitrosoguanidine. 241 92

A study was undertaken to determine the ability of the DNA hypomethylating drug 5-aza-2'-deoxycytidine (5-azadCyd) to induce antigen expression in a high proportion of treated tumor cells and to evaluate if this effect could be mimicked by the drug hydroxyurea (HU) which is a genomic DNA hypermethylating agent. Induction of heritable changes in gene expression by 5-azacytidine or the 2'-deoxy analogue (5-azadCyd), at least in some cases, may not be necessarily due to their hypomethylating properties, but to some other induced high frequency genetic change which occurs when DNA synthesis or repair is perturbed. A comparison of 5-azadCyd and HU effects on human and murine tumors was chosen for this study. The phenotypic properties examined with the above treatments were (a) induction of a Mr 110,000 antigen, detected with M111 antibody, in a variant subpopulation (SMeLus7) of human melanoma cells which fail to maximally express this antigen (M111). The parent cell line, MeWo, and other MeWo-derived variant cell cell lines do not demonstrate a similarly inducible phenotype; and (b) induction of class I major histocompatibility complex antigens in a population of mouse mammary adenocarcinoma cells which normally fail to express these antigens. The results showed that 5-azadCyd was effective in inducing antigen expression in both systems whereas HU was effective (and equally so) only in the human melanoma cell line system. In these treatments 5-azadCyd was demonstrated to transiently hypomethylate the same human melanoma cell line whereas HU hypermethylated genomic cytosines. The results suggest that some of the reported effects of 5-azacytidine or 5-azadCyd in inducing very high frequency heritable phenotypic alterations may not necessarily be related to the drugs' ability to cause DNA hypomethylation. The implications of these results are discussed in terms of the use of 5-azacytidine or 5-azadCyd and the effects of chemotherapy on tumor progression and metastasis.
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PMID:Heritable high frequency modulation of antigen expression in neoplastic cells exposed to 5-aza-2'-deoxycytidine or hydroxyurea: analysis and implications. 245 61

Interferon-gamma (IFN-gamma) can enhance the experimental metastatic ability of B16 melanoma. The in vitro treatment with IFN-gamma of four clones derived from the murine mammary adenocarcinoma TS/A increased the number of lung colonies observed after intravenous injection in syngeneic mice. The spontaneous metastatic ability of these clones was not altered by the IFN-gamma pretreatment nor by daily intratumor injection of low-dose IFN-gamma. The experimental metastatic ability in nude mice of the human rhabdomyosarcoma cell line RD was decreased by in vitro pretreatment with IFN-gamma. To study the role played by major histocompatibility complex gene products in the IFN-gamma-mediated enhancement of B16 experimental metastasis, a mutant B16 clone, B78H1, was transfected with the H-2Kb gene. B78H1 cells are not capable of expressing H-2b even after treatment with IFN-gamma; IFN-gamma readily induced high levels of H-2Kb in a set of transfected clones, but did not enhance their experimental metastatic ability.
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PMID:Modulation by IFN-gamma of the metastatic ability of murine, human, and H-2-transfected tumor cells. 251 Mar 84

Cytolytic T lymphocytes (CTL) cause cytolysis of foreign or virus-infected syngeneic cells when recognition of the target plus major histocompatibility complex (MHC) occurs via the T-cell receptor (TCR). The recognition event leads to intimate contact between the two cells and activation of the cytolytic effector. Activation and target cell lysis can also occur in the presence of antibodies to the TCR. This is accomplished by bridging the effector cell TCR to the target cell FcR by an anti-TCR monoclonal antibody (MoAb). Recent findings have placed the role of the FcR in this event in a questionable light. We confirm the importance of Fc gamma R by demonstrating that: (a) melanoma cells are killed by CTL clones in the presence of anti-TCR-CD3 antibodies only when the melanoma cells express the Fc gamma R on their surface; (b) native Ig, heat-aggregated Ig, or an Fc fragment from an antibody expressing the same isotype as the anti-TCR antibody can block the killing of high avidity Fc gamma RI-bearing cells mediated by anti-TCR antibody (F23.1); and (c) anti-Fc gamma R MoAb (2.4G2) and a truncated soluble Fc gamma RII molecule inhibit the killing of low-avidity Fc gamma RII-bearing cells mediated by anti-CD3 MoAb (145-2C11). Thus, we show that both high-avidity Fc gamma RI and low-avidity Fc gamma RII can mediate sideways killing depending upon the isotype of the anti-TCR antibody and the type of FcR present on the target cell surface.
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PMID:Sideways killing: the cytolysis of Fc receptor-bearing cells through bridging to cytolytic T lymphocytes by antibodies specific for the T-cell receptor-T3 complex. 252 7


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