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

Previous studies have shown that recognition of melanoma by cytotoxic T lymphocytes may be restricted by HLA-A1, A2 and other HLA antigens. The present study examined the cytotoxic specificity and major histocompatibility complex restriction of cloned cytotoxic T lymphocytes (CTL) isolated from a patient with the HLA phenotype A3,31 who had been immunized with a vaccine prepared from HLA-A1,3 melanoma cells. Cytotoxic assays against HLA-typed allogeneic melanoma cells indicated that cloned CTL from the patient were able to kill allogeneic melanoma cells expressing HLA-A1 but not other HLA-A1-positive cells. Studies on a representative clone indicated that proliferation and cytokine (tumour necrosis factor alpha) production in response to melanoma cells was also associated with HLA-A1 on melanoma cells. Response to the melanoma cells was associated with interleukin-4 (IL-4) rather than IL-2 production. The antigen recognized in the context of HLA-A1 on allogeneic melanoma cells was detected in cytotoxic assays on cells from 9 of 12 HLA-A1+ melanoma cell lines and did not appear to be the product of the MAGE-1 or -3 genes. These findings suggest that T cells can recognize melanoma antigens in the context of alloantigens and that allogeneic vaccines containing "immunodominant" alloantigens may generate CTL that are ineffective against autologous melanoma. The study does not, however, exclude the possibility that CTL with specificity to the latter may be activated by allogeneic vaccines, and further studies are needed to answer this question.
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PMID:T cell recognition of melanoma antigens in association with HLA-A1 on allogeneic melanoma cells. 820 60

Many human as well as experimental tumours, including melanoma, express reduced levels of major histocompatibility complex (MHC) Class I antigens. Decreased MHC Class I antigen expression may be selected during neoplastic progression because it allows tumour cells to escape killing by cytotoxic T lymphocytes. Furthermore, the regulatory role of MHC Class I antigens in the proliferation of T cells suggests that abnormalities in MHC Class I antigen expression may play a role in the disordered proliferation of malignant cells and in their metastatic potential by non-immunological mechanisms. This paper reviews some of the available evidence supporting the concept of non-immune functions of MHC Class I antigens in the biology of malignant cells, with emphasis on experimental models for metastatic melanoma.
Melanoma Res 1993 Aug
PMID:Modulation by MHC class I antigens of the biology of melanoma cells. Non-immunological mechanisms. 821 62

The survival of C57BL/6 mice (H-2b) bearing B16 melanoma (H-2b) was prolonged if the animals were treated solely by immunization with an interleukin-2 (IL-2)-secreting allogeneic cell construct that expressed melanoma-associated antigens (MAA) along with major histocompatibility complex (MHC) class-I determinants (H-2k; RLBA-IL-2 cells). This was the case if the mice were immunized simultaneously with, or 6 days following, the injection of viable B16 cells. Under similar conditions, the survival of tumor-bearing mice immunized with an allogeneic cell construct (H-2k) that expressed MAA but did not secrete IL-2 (RLBA-ZipNeo cells), or with an allogeneic construct (H-2k) that secreted IL-2 but did not form MAA (LM-IL-2 cells), was also prolonged. However, in these instances, the period of survival was significantly shorter than that of mice immunized with the cell construct that combined IL-2 secretion with the expression of MAA. Tumor-bearing mice immunized with non-transfected LM(TK-) cells (H-2k), or irradiated B16 cells (H-2b) failed to survive longer than untreated mice. Although the survival of the treated animals was prolonged, in most instances tumor growth recurred. The recurrent tumors in mice treated with the allogeneic cell constructs formed melanin and were histologically indistinguishable from tumors in untreated mice. Cells from the recurrent tumors were resistant to further immunotherapy and to cytotoxic effector cells obtained from the spleens of mice immunized with the same cellular immunogen used initially. The injection of IL-2-secreting syngeneic B16 cells into C57BL/6 mice invariably resulted in the appearance of non-IL-2-secreting melanomas. Under similar circumstances, tumors failed to develop in C57BL/6 mice injected with IL-2-secreting, or non-secreting, allogeneic cell constructs. Thus, the expression of allogeneic antigens protected the mice from growth of the cellular immunogens.
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PMID:Immunization with interleukin-2-secreting allogeneic mouse fibroblasts expressing melanoma-associated antigens prolongs the survival of mice with melanoma. 824 84

Direct gene transfer offers the potential to introduce DNA encoding therapeutic proteins to treat human disease. Previously, gene transfer in humans has been achieved by a cell-mediated ex vivo approach in which cells from the blood or tissue of patients are genetically modified in the laboratory and subsequently returned to the patient. To determine the feasibility and safety of directly transferring genes into humans, a clinical study was performed. The gene encoding a foreign major histocompatibility complex protein, HLA-B7, was introduced into HLA-B7-negative patients with advanced melanoma by injection of DNA-liposome complexes in an effort to demonstrate gene transfer, document recombinant gene expression, and determine the safety and potential toxicity of this therapy. Six courses of treatment were completed without complications in five HLA-B7-negative patients with stage IV melanoma. Plasmid DNA was detected within biopsies of treated tumor nodules 3-7 days after injection but was not found in the serum at any time by using the polymerase chain reaction. Recombinant HLA-B7 protein was demonstrated in tumor biopsy tissue in all five patients by immunochemistry, and immune responses to HLA-B7 and autologous tumors could be detected. No antibodies to DNA were detected in any patient. One patient demonstrated regression of injected nodules on two independent treatments, which was accompanied by regression at distant sites. These studies demonstrate the feasibility, safety, and therapeutic potential of direct gene transfer in humans.
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PMID:Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. 824 44

A number of different cytokines, including IL-1 alpha and beta, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IFN-alpha, -beta and gamma, TNF-alpha -beta, and TGF-beta 1, can modulate the expression of distinct cell surface antigens of normal and neoplastic cells. Both induction/increase of expression and reduction of expression can be achieved depending on the antigen and on the cytokine. Antigens subjected to the modulating activity of cytokines include distinct families of cell surface structures such as the molecules coded by the major histocompatibility complex (MHC), the superfamily of adhesion receptors that regulate cell-cell and cell-matrix interaction, receptors for cytokines and growth factors and tumor-associated antigens. The modulating activity of cytokines is a consequence of their influence on gene expression, protein synthesis, membrane expression and shedding of antigens from the cell surface. The changes of phenotype due to the action of cytokines can influence the signalling pathways dependent on the expression and function of cell surface structures. Therefore, the antigen modulating activity of cytokines can thoroughly affect the biological behavior of normal and neoplastic cells. As described here, most of the modulating effects of cytokines on different cell surface structures and the functional consequences of antigenic modulation can be verified in human malignant melanoma cells.
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PMID:The role of cytokines in the modulation of cell surface antigens of human melanoma. 827 6

The adoptive transfer of tumor-infiltrating lymphocytes (TILs) with interleukin-2 (IL-2) has antitumor activity in some patients with metastatic melanoma. We have analyzed molecular mechanisms of TIL recognition of human melanoma. Some cultured TILs specifically lysed autologous and some allogeneic melanomas sharing a variety of class I major histocompatibility complex (MHC) molecules. HLA-A2-restricted melanoma-specific TILs lysed many HLA-A2+ melanoma cell lines from different patients but failed to lyse HLA-A2- melanoma and HLA-A2+ nonmelanoma cell lines. However, these TILs were capable of lysing many naturally HLA-A2- melanomas after introduction of the HLA-A2.1 gene by vaccinia virus. These results indicate that shared melanoma antigens (Ag) are expressed in melanomas regardless of their human leukocyte antigen types. In order to identify these shared melanoma Ags, we have tested some known proteins expressed in melanoma. Expression of tyrosinase or HMB45 Ag correlated with lysis of TILs. We are also attempting to isolate antigenic peptides by high performance liquid chromatography separation and genes encoding melanoma Ag by cDNA expression cloning. The T-cell component of the antimelanoma response was also analyzed by determining the genetic structure of the T-cell receptor (TCR) used by melanoma TILs. However, we did not observe common TCR variable region usage by different melanoma TILs. We could establish melanoma cell clones and lines resistant to TIL lysis due to the absence of or defects in the expression of Ag, MHC, or beta 2-microglobulin molecules. These data indicate multiple mechanisms for melanoma escape from T-cell immunosurveillance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:T-cell recognition of human melanoma antigens. 828 Jul 5

Dendritic epidermal T-cells (DETC) are a unique population of T-cells that reside normally in mouse epidermis and express a gamma delta T-cell receptor. We have reported previously that DETC acquire in culture the capacity to lyse the YAC-1 lymphoma, a conventional target for natural killer cells. The aim of the present study was to characterize this cytotoxic potential, using a spectrum of skin-derived mouse tumors. Cytotoxicity was measured by a 51Cr release assay and by the visual assessment of target cell lysis. Long-term DETC lines, established from CBA, AKR, and BALB/c mice by mitogenic stimulation and repeated feeding with interleukin 2 (5 units/ml), were used as effectors. Skin-derived tumor targets included 5 melanoma lines and the transformed keratinocyte line Pam 212. Each DETC line lysed skin-derived tumors as well as YAC-1 targets effectively in the 18-h 51Cr release assay, and target lysis occurred in a non-major histocompatibility complex-restricted manner. By contrast, freshly isolated spleen cells lysed YAC-1 but not skin tumor targets. Moreover, confluent monolayers of melanoma or Pam 212 targets were disrupted completely by added DETC lines but not by spleen cells. The cytolytic activity of DETC appeared to be specific for tumor cells, since normal mouse keratinocyte monolayers remained intact under the same conditions. Finally, DETC freshly isolated from skin failed to exhibit significant cytotoxicity but acquired this capacity 10-14 days after mitogenic stimulation and feeding with interleukin 2 (5 units/ml). We conclude that DETC possess the potential to recognize, bind, and lyse tumor cells that originate in skin.
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PMID:Killing of skin-derived tumor cells by mouse dendritic epidermal T-cells. 835 30

Lysis of autologous and human leucocyte antigen (HLA)-matched allogeneic melanomas by cultured human tumor-infiltrating leukocytes (TIL) suggests that shared melanoma antigens (Ag) exist and are recognized by TIL in the context of self major histocompatibility complex (MHC) molecules. We have recently shown that cytokine release by TIL is another indicator of the specific interaction with autologous tumor. To determine if recognition of shared melanoma Ag can also induce cytokine release, seven melanoma TIL, which lysed autologous tumor, were co-cultured with autologous tumor or with 7-12 HLA-matched or unmatched melanoma stimulators for 6-24 h. Supernatants were collected and assayed by ELISA for the presence of granulocyte/macrophage colony stimulating factor (GM-CSF), interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-4, and IL-6. Among five of six melanoma TIL for which autologous tumor was available, autologous melanoma cells stimulated specific release of at least one of three cytokines: GM-CSF, IFN-gamma, and TNF-alpha. Neither IL-4 nor IL-6 secretion by three TIL cultures tested was enhanced upon contact with tumor. For six of seven TIL cultures, HLA-matched allogeneic melanomas also stimulated significant cytokine release; HLA-A1, -A2, -A24, -B8, and -Cw7 were identified as possible restriction elements. The cytokine secretion induced by both autologous and allogeneic HLA-matched melanomas could be blocked by an anti-MHC I antibody. These data suggest that cytokines can be specifically released by TIL recognizing a shared melanoma antigen in the context of self MHC molecules.
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PMID:Specific release of cytokines by lymphocytes infiltrating human melanomas in response to shared melanoma antigens. 843 28

The B16-BL6 melanoma, like most spontaneously arising tumors, is poorly immunogenic and expresses low levels of major histocompatibility complex (MHC) antigens. Treatment of cells of this tumor in vitro by hydrostatic pressure in the presence of adenosine 2',3'-dialdehyde (oxAdo), a membrane-impermeant crosslinker, caused elevated projection of MHC and a specific tumor antigen as demonstrated by flow-cytometric analysis. Maximum projection of both the MHC and the tumor antigens could be reached by application of 1200 atm for 15 min in the presence of 20 mM oxAdo. It is not yet clear whether this passive increase in availability of antigens on the cell surface originated from a dormant pool of antigens in the plasma membrane or from pressure-induced fusion of antigen-rich intracellular organelles (e.g. the endoplasmic reticulum). The immunogenic properties of the antigen-enriched B16-BL6 cells are described in the following paper.
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PMID:Increased projection of MHC and tumor antigens in murine B16-BL6 melanoma induced by hydrostatic pressure and chemical crosslinking. 847 15

In the preceding paper we have demonstrated an increase in presentation of both major histocompatibility complex antigens (MHC) and a tumor-associated antigen of the weakly immunogenic B16 melanoma by a straight-forward technique. The method consists in modulating the tumor cell membrane by hydrostatic pressure and simultaneous chemical crosslinking of the cell-surface proteins. In B16-BL6 melanoma, the induced antigenic modulation was found to persist for over 48 h, which permitted the evaluation of the ability of modified B16-BL6 cells to induce immunity against unmodified B16-BL6 cells. In the present study, we have shown that a significant systemic immunity was induced only in mice that were immunized with modified B16-BL6 melanoma cells, whereas immunization with unmodified B16-BL6 cells had only a marginal effect when compared to the results in control sham-immunized mice. The induced immunity was specific since a single immunization affected the growth of B16-BL6 tumors but had no effect on MCA 106, an antigenically unrelated tumor. The addition of interleukin-2 to the immunization regimen had no effect on the antitumor responses induced by the modified B16-BL6 cells. The cell-mediated immunity conferred by immunization with treated B16-BL6 cells was confirmed in experiments in vitro where splenocytes from immunized mice could be sensitized to proliferate by the presence of B16-BL6 cells. In addition, the altered antigenicity of these melanoma cells appeared to correlate with their increased susceptibility to specific effectors. Thus, 51Cr-labeled B16-BL6 target cells, modified by pressure and crosslinking, in comparison to control labeled target cells, were lysed in much greater numbers by effectors such as lymphokine-activated killer cells and allogeneic cytotoxic lymphocytes (anti-H-2b), while such cells remained resistant to lysis by natural killer cells. Our findings indicate that the physical and chemical modifications of the tumor cells that are described here may be considered as a simple yet effective method for the preparation of tumor vaccines, which could be applied in tumor-bearing hosts.
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PMID:Induction of cell-mediated immunity against B16-BL6 melanoma in mice vaccinated with cells modified by hydrostatic pressure and chemical crosslinking. 847 16


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