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

Cytotoxic T lymphocytes (CTLs) recognize peptide antigens associated with cell surface major histocompatibility complex (MHC) molecules. The identification of tumor cell-derived peptides capable of eliciting anti-tumor CTL responses would enable the design of antigen-specific immunotherapies. Our strategy to identify such potentially therapeutic peptides relies on selecting high-affinity MHC binders from known tumor-associated antigens. These peptides are subsequently tested for their ability to induce CTLs capable of killing tumor cells. With this strategy, we have identified a nine-residue epitope, derived from the product of the tumor-associated gene MAGE-3, which has the capacity to induce in vitro CTLs that kill melanoma and other tumor cell lines. These results show the primary in vitro induction of tumor-specific human CTLs and illustrate the feasibility of ex vivo antigen-specific approaches to the immunological therapy of cancer.
 ...
PMID:Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. 751 Aug 85

MAGE-1 is a gene that encodes an antigen on a melanoma cell line that is recognized by cytolytic T-cells. We have used a reverse transcription-polymerase chain reaction assay to analyze expression of the MAGE-1 gene by cell lines from different types of tumors, melanomas from different stages of disease progression, normal diploid cell lines, and melanocyte and nevus tissue from which malignant melanomas are derived. MAGE-1 is expressed by melanoma tissue from all stages of disease, but not melanocytes, nevus tissue, or any normal diploid cell line tested. A fraction of tumor lines derived from various epithelial and neuroectodermal malignancies expressed MAGE-1 but not peripheral blood cells from patients with melanoma. 5-Aza-2'-deoxycytidine (DAC), a demethylating agent, was capable of inducing MAGE-1 expression by a MAGE-1-negative melanoma cell line 888-mel as well as by a number of other melanoma cell lines. At an optimum concentration of 1 microM DAC, MAGE-1 expression was detectable by 24 h, plateaued by 72 h, but remained high for two weeks after removal of DAC from treated 888-mel cells, consistent with induction by demethylation. With the exception of tumor-infiltrating leukocytes, no normal diploid cell line could be induced with DAC to upregulate MAGE-1 expression. DAC-treated 888-mel cells were lysed by a MAGE-1-specific major histocompatibility complex restricted cytolytic T-cell clone, whereas control untreated cells were not, suggesting that production of the antigen encoded by the MAGE-1 gene was induced by DAC and that it was presented in association with major histocompatibility complex class I molecules at the cell surface for T-cell recognition.
 ...
PMID:Expression of the MAGE-1 tumor antigen is up-regulated by the demethylating agent 5-aza-2'-deoxycytidine. 751 Oct 51

Malignant transformation of melanocytes may be associated with changes in the expression of major histocompatibility complex (MHC) HLA class I antigens. Interest in the characterization of abnormalities in the expression of MHC class I by melanoma cells has been rekindled by the current emphasis on the application of T-cell-based immunotherapy to melanoma. Here, Soldano Ferrone and Francesco Marincola review defects in class I expression as described in melanoma cells, as well as the molecular mechanisms, functional significance and clinical implications of such defects.
 ...
PMID:Loss of HLA class I antigens by melanoma cells: molecular mechanisms, functional significance and clinical relevance. 757 53

The coexistence of tumor-specific immunity with a progressing tumor is observed in most experimental systems and remains one of the major paradoxes of tumor immunology. Expression of several surface molecules on melanoma cells, e.g., intercellular adhesion molecule 1 (ICAM-1) or major histocompatibility complex (MHC) class II, has been associated with an aggressive tumor growth and an reduced host antitumor response. HLA class I expression is also frequently altered in melanoma compared to melanocytes. Given the central role of these molecules in the restriction of T cell recognition, regulation of tumor HLA class I expression might also be a strategy for the evasion of immune surveillance by the malignant cells. The fact that it is now possible to clone antigen-specific T cells from tumor patients, as well as the relevant autologous tumor cell lines, enabled us to establish a model system to investigate possible tumor escape mechanisms from immunosurveillance. Using this system, we were able to demonstrate that purified soluble ICAM-1 or 12-fold-concentrated cell-free melanoma supernatants, containing shed ICAM-1, were able to inhibit conjugate formation between T cell clones and the autologous melanoma cells as efficiently as monoclonal antibodies against CD11a, Soluble ICAM-1 also abrogated the MHC-restricted killing of the melanoma by T cell clones. We further observed that a number of CD4+ T cell clones and melanoma cell lines established from the same tumors form conjugates with each other, leading to an increase of [Ca2+]i in the T cell clone; however, this interaction failed to induce interleukin-2 production or proliferation of the T cell clone. Furthermore, this interaction rendered the T cell clone unresponsive to subsequent stimulation. All these effects were MHC class II restricted. Therefore, the melanoma was capable of delivering antigen-specific signals to the T cell clone, but did not deliver the costimulatory signals, e.g., a B7/CD28 interaction, necessary for full T cell activation. Transfection of the melanoma with an expression vector containing a B7 cDNA with subsequent B7 expression on its cell surface renders the melanoma a fully competent antigen-presenting cell which is able to induce a nuclear factor binding to the interleukin-2 promoter in the specific T cell clone, followed by enhanced interleukin-2 transcription, synthesis, and T cell proliferation.
 ...
PMID:Lymphocyte-melanoma interaction: role of surface molecules. 759 91

We have previously shown that administration of cyclosporine A (CsA) plus interferon-gamma (IFN) after chemotherapy to mice bearing B16 melanoma results in the generation of cells with major histocompatibility complex (MHC)-unrestricted cytotoxicity in vitro and in vivo; the antitumor effect of these cells could be attenuated by normal spleen cells. This study shows that antitumor effect after treatment with CsA plus IFN after chemotherapy was mediated by T and natural killer (NK) cells, both in vitro and in vivo. Infusion of purified T or NK cells into secondary recipients after chemotherapy resulted in a significant control in the dissemination of tumor as compared to chemotherapy alone. The antitumor potential of NK cells was at least 10 times greater than that of T cells. The effector cells could inhibit the proliferation of tumor cells in vitro without a contact between the effector and tumor cells, suggesting that antitumor effect in this system was partly related to the secretion of cytotoxic factors by the effector cells. Infusion of normal spleen cells inhibited the antitumor effect of adoptively transferred effector cells. This study defines the nature of effector cells involved in mediating the antitumor effect in this model; the optimal efficacy of these cells in the recipient is possibly related to the abolition of a suppressor system by chemotherapy.
 ...
PMID:Induction of antitumor effect by treatment with cyclosporine A plus interferon-gamma after chemotherapy: role of cytotoxic cells. 761 40

Ethanol (20% w/v) given to female C57BL/6 mice in their drinking water reduces splenic natural killer (NK) cell cytolytic activity after 2, 4, and 10 weeks of consumption. This reduction is transient because the levels of NK cell cytotoxicity from ethanol-consuming mice are nearly equal to those of water-drinking mice after splenocytes were incubated in 1000 IU/ml of recombinant interleukin-2 (rIL2) for 16-18 hr. In this study, mice were given 20% w/v ethanol in the drinking water for 2 weeks. Splenic NK cells were enriched up to 88% by negative selection based on surface expression of NK1.1. Enriched NK cells were expanded in rIL2 for 6 days. Lymphokine-activated killer (LAK) cells from both ethanol-consuming and water-drinking mice were > 95% NK1.1+. LAK cell cytolytic activity was significantly lower against NK-insensitive P815 mastocytoma [6.67 +/- 2.18 vs. 17.21 +/- 1.8 lytic units (LUs), p < 0.01], moderately NK-sensitive B16 melanoma (25.3 +/- 6.6 vs. 66.2 +/- 14.2 LU, p < 0.05), and NK-sensitive YAC-1 lymphoma targets (80.5 +/- 34.7 vs. 177.0 +/- 43.6 LU, p < 0.005) in cells from ethanol-consuming mice compared with water-drinking controls. Ethanol consumption did not affect the morphology or phenotype of LAK cells with respect to surface expression of NK1.1, B220, CD3, CD25, CD11a, CD54, CD45RB, or class I major histocompatibility complex.
 ...
PMID:Ethanol consumption reduces the cytolytic activity of lymphokine-activated killer cells. 762 74

In an effort to enhance the antigenicity of canine tumor cells, canine interferon-gamma (CnIFN-gamma) was applied in vitro to seven canine mammary tumor (CMT) and two canine melanoma (CML) cell lines. Surface expression of major histocompatibility complex (MHC) antigens and tumor-associated antigens (TAA) was measured by a flow cytometric fluorescence assay using commercially available anti-MHC antibodies, and anti-canine TAA monoclonal antibodies generated against CMT and CML cell lines. Compared to constitutive antigen levels in untreated cells, treatment with CnIFN-gamma resulted in increased expression of MHC class I and II antigens (up to 19- and 167-fold, respectively) and a TAA (up to 5-fold) by CMT cell lines, and increased expression of class I antigen (131-fold) by one CML and of class II antigen (18-fold) by the other CML cell line. Expression of MHC antigens and a TAA by tumor cells was increased by Cn-IFN-gamma treatment, and such an increase may be of potential benefit in tumor cell recognition and rejection by the immune system.
 ...
PMID:Modulation by canine interferon-gamma of major histocompatibility complex and tumor-associated antigen expression in canine mammary tumor and melanoma cell lines. 764 83

The response of mouse T cells to the superantigen staphylococcal enterotoxin A (SEA) requires 1000-fold higher concentrations compared to human T cells. In order to develop a sensitive model for SEA studies in mice, the immunopharmacology has been studied in T-cell receptor (TcR) V beta 3 transgenic (TGV beta 3) and non-transgenic (non-TG) C57Bl/6 mice. The frequency of SEA-responsive T cells in the TGV beta 3 mice exceeded 90%, whereas a 10-fold lower frequency was seen in normal C57Bl/6 mice. Nanograms of SEA injected intravenously into TGV beta 3 mice induced strong cytolytic T lymphocyte (CTL) activity against SEA-coated major histocompatibility complex (MHC) class II+ B-lymphoma cells, whereas administration of 1000-fold higher amounts of SEA to non-TG littermates or normal C57Bl/6 mice induced only a moderate response. Kinetic analysis demonstrated that the CTL activity was more rapidly detectable in TG mice, but substantial levels were seen 2 days after SEA injection in both TGV beta 3 and non-TG mice. The cytotoxic T-cell response induced by SEA in TGV beta 3 and non-TG mice was completely MHC class II dependent, as SEA-coated MHC class II-transfected syngeneic B16 melanoma cells but not untransfected B16 cells were sensitive to lysis. Large amounts of tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) accumulated in serum of TGV beta 3 mice after injection of 10 ng SEA, whereas only marginal amounts were recorded in non-TG even after injection of 100 micrograms SEA. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated that SEA-induced TNF-alpha and IFN-gamma mRNA reached maximal levels 1 hr after SEA administration in TGV beta 3 mice, whereas peak serum levels of TNF-alpha and IFN-gamma proteins were recorded after 2 hr. Comparison of the mRNA levels of a panel of cytokines in the TGV beta 3 and non-TG mice revealed that almost similar amounts of interleukin-1 (IL-1) were induced in both strains, whereas IL-4 was only detected at significant levels in the TGV beta 3 mouse. The results suggest that TGV beta 3 mice are suitable for studying in vivo immune responses to superantigens at concentrations comparable to the potent effects elicited in humans. Moreover, this model is useful for detailed studies on the dynamic regulation of T-cell activation and anergy induced by superantigens.
 ...
PMID:Immunopharmacology of the superantigen staphylococcal enterotoxin A in T-cell receptor V beta 3 transgenic mice. 769 31

The growth of a potentially antigenic tumor in an immunocompetent host is taken as an indication that the malignant cells 'escaped' the cytotoxic capacity of the immune system. An increase in our knowledge of the means by which antigens are processed and expressed allows a greater understanding of the mechanism that enables tumor cells to avoid host immunity. It provides a rationale for new, more innovative forms of treatment. Antigenic determinants are presented to cytotoxic T lymphocytes (CTLs) in the context of class I determinants, structures specified by genes within the major histocompatibility complex. Potentially antigenic tumors may express lower levels of class I determinants than surrounding non-neoplastic cells. As a consequence, the tumor-associated T cell epitopes formed by the malignant cells may go unrecognized by tumor-specific CTLs. The introduction of genes specifying class I determinants into low class I expressing tumor cells increased class I expression and restored the cells' immunogenic properties. Treatment of low class I expressing cells with interferon-gamma, or the introduction of the interferon-gamma gene into the cells resulted in an increase in the expression of class I determinants as well, and, as a consequence, recognition of the malignant cells by the immune system. Nevertheless, an immunotherapeutic strategy that stimulated a single anti-tumor effector mechanism might be unable to eliminate a heterogeneous tumor cell population. To investigate this point, mice with melanoma were treated with a mixture of interferon-gamma-secreting and IL-2-secreting cellular immunogens. The animals survived significantly longer than mice with melanoma treated with either the IL-2 or interferon-gamma-secreting immunogens alone. The complexity of the problem was illustrated by the fact that although survival was prolonged, tumor growth recurred in each instance.
 ...
PMID:Neoplastic cells that express low levels of MHC class I determinants escape host immunity. 770 41

In an effort to enhance the generation of tumor-reactive T-lymphocytes for adoptive immunotherapy, we examined the effects of in vivo transfection of an allogeneic major histocompatibility complex (MHC) class I gene (H-2Ks) of the poorly immunogenic B16BL6 (BL6) melanoma of H-2b origin. Cells from lymph nodes (LNs) draining these tumors after transfection were assessed in adoptive immunotherapy experiments for tumor reactivity after sequential activation with anti-CD3 monoclonal antibody (mAb) followed by culture in interleukin (IL)-2. H-2Ks lipofection of progressively growing BL6 subcutaneous tumors did not reduce tumorigenicity. However, in vivo lipofection of BL6 by intratumor inoculation or admixture of H-2Ks cDNA/liposome complexes and tumor cells prior to inoculation resulted in enhanced development of sensitized T-lymphocytes in the draining LN, which mediated the reduction of the numbers of established 3-day parental lung metastases in six of six experiments. In subsequent studies, in vivo transfection of BL6 with naked H-2Ks cDNA was found to be more effective than lipofection in eliciting sensitized T-cells in the draining LN. Admixture of liposomes alone or control plasmid DNA did not have an adjuvant effect similar to H-2Ks cDNA. Relative tumor transfection efficiency was assessed by an indirect assay with the chloramphenicol acetyltransferase (CAT) reporter gene. BL6 tumors were more efficiently transfected by intratumor inoculation with naked cDNA compared with lipofection. In summary, in vivo allogenization of the poorly immunogenic BL6 tumor resulted in enhanced generation of therapeutic T-cells effective in the treatment of parental tumor.
 ...
PMID:Generation of therapeutic T-lymphocytes after in vivo tumor transfection with an allogeneic class I major histocompatibility complex gene. 772 1


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>