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)

Ly-6C+ cells constitute 13 +/- 3% of freshly isolated (CBA x C57BL/6)F1 mouse spleen leukocytes. Three distinct populations were identified: CD3 epsilon +NK-1.1- conventional T cells (6%), CD3 epsilon -NK-1.1- granulocytes (5%) and CD3 epsilon +NK-1.1+ T cells (approximately 2%). The CD3 epsilon +NK-1.1+ cells displayed a predominantly large granular leukocyte morphology and were the only Ly-6C+ cell subset identified by MAb 2B6-F2 to spontaneously lyse the NK-sensitive YAC-1 tumour in vitro. On further phenotypic analysis, these cells co-expressed high levels of TCRV beta 8.1/8.2 and CD11b, moderate levels of CD90 and low levels of CD4 or CD8. The removal of CD4+ and CD8+ cells prior to Ly-6C+ cell sorting showed that it was the CD4-CD8- double-negative (DN) CD3 epsilon +NK-1.1+ T-cell subset which was responsible for killing YAC-1. These results indicate that we have identified a DN Ly-6C+ subset of the recently designated NK-1.1+TCR alpha beta low natural T (NT) cells, which are capable of natural cell-mediated cytotoxicity (NCMC) against the NK-sensitive YAC-I tumour in vitro. Additionally, these cells mediated the in vitro killing of 2 further NK-sensitive tumours, murine B16 melanoma and human Jurkat T lymphoma. YAC-1 and Jurkat expressed Fas and were susceptible to anti-Fas MAb or rhuman Fas ligand (rhFasL)-induced lysis. Furthermore, anti-human Fas MAb M3 was shown to block sorted Ly-6C+ splenocyte in vitro killing of Jurkat. In contrast, B16 did not express cell-surface Fas and was resistant to anti-Fas MAb-induced lysis. Taken together, these results show that not only do Ly-6C+ NT cells kill NK-sensitive tumours in vitro but they mediate this activity via multiple cytotoxic mechanisms including Fas.
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PMID:Natural cell-mediated cytotoxicity (NCMC) against NK-sensitive tumours in vitro by murine spleen Ly-6C+ natural T cells. 903 54

In the present study an acidic polysaccharide ginsan, with a molecular weight of 150,000, devoid of lectin properties, was purified from Panax ginseng C.A. Meyer (Araliaceae). Ginsan induced the proliferation of T cells and B cells. Spleen cells became cytotoxic to a wide range of tumor cells without major histocompatibility complex-restriction after 4 or 5 days culture in vitro with ginsan. For the generation of these ginsan-activated killer (AK) cells adherent macrophages and CD4+ cells were needed as accessory cells. The generation of ginsan-AK cells was blocked in the presence of anti-IL-2, anti-IFN gamma, anti-IL-1 or anti-TNF alpha antibodies, showing the importance of these cytokines in the process. The surface phenotypes of the 4 day-cultured ginsan-AK cells was Thy1+, AsGM1+, CD8+, which is distinct from rIL-2 induced lymphokine activated killer (LAK) cells that were CD8. The ginsan also activated macrophages to produce reactive nitrogen intermediates and become tumoricidal. It also exhibited significant in vivo antitumor activity against B16 melanoma cells lines, and in the benzo(a)pyrene-induced autochthonous lung tumor model, at much lower doses than the maximum tolerate doses. Indeed, no mice died, which injected with ginsan at 1g/kg body weight intraperitoneally. In conclusion, 'ginsan' could potentially be an ideal nontoxic antineoplastic immunostimulator by activating multiple effector arms of the immune system.
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PMID:Activation of multiple effector pathways of immune system by the antineoplastic immunostimulator acidic polysaccharide ginsan isolated from Panax ginseng. 906 72

Determinants of T cell responses to tumor cells remain largely unknown. In the present study we have used long-term cultures of human melanoma cells and autologous peripheral blood lymphocytes to examine the influence of cytokines with T cell growth activity on the phenotype and cytotoxic and proliferative response of T cells to melanoma. It was found that addition of interleukin-4 (IL-4) inhibited the response of CD8+ T cells and promoted the response of the CD4 subset. IL-2 or IL-7 was effective in increasing melanoma-specific cytotoxic T lymphocyte (CTL) activity in cultures where CD8 T cells were predominant, whereas IL-4 followed by IL-2 was most effective in cultures where CD4 T cells predominated. IL-10 or IL-12 inhibited proliferation and CTL activity against melanoma in long-term cultures. The effects of IL-12 were reproduced in long-term cultures of T cells stimulated with mAb against CD3 and were shown to depend on prior exposure of T cells to IL-12 before IL-2. As yet unidentified factors, such as co-factor expression on melanoma, appear to be as important as exogenous cytokines in determining the nature of T cell responses to melanoma. These results suggest that analysis of responses in long-term culture may assist in defining the role of key cytokines and other determinants of immune responses to melanoma.
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PMID:Contrasting effects of T cell growth factors on T cell responses to melanoma in vitro. 906 6

Interferon-gamma (IFN-gamma) has the most potent immunomodulatory activity of all the interferons. This phase II-B study was performed to define time- and dose-dependent immunomodulatory effects mediated by IFN-gamma in a subset of patients with melanoma treated in the dose-seeking therapeutic trial conducted by the Eastern Cooperative Oncology Group E4687 (13). The effects of IFN-gamma (Genentech, San Francisco, CA) were evaluated for phenotype and function of peripheral blood lymphocytes obtained twice prestudy, and on days 2, 9, and 29 of IFN-gamma therapy for 50 patients. Early significant increases in CD4/CD8 ratio (p = 0.001) were noted, largely due to a rise in CD4+ and fall in CD8+ T-cell populations sustained through day 29 at only the lowest dosage. Increased natural killer cell (NK) activity (p = 0.001 on day 9; p = 0.01 on day 29) was accompanied by durable increases in circulating activated NK cells (CD56+DR+% p = 0.001, day 9; p = 0.001, day 29). After initial depression of CD56+ and CD16+ cells on day 2, the total percent of CD56+ and CD16+ cells increased significantly by day 29. Increases in NK cell activity were maximal at doses > or =0.1 mg. Monocyte CD14+ expression of DQ+ rose early (p = 0.011 and 0.001 on days 2 and 9), accompanied by elevation in CD14+DR+ cells that was less significant. Immunomodulatory effects of IFN-gamma reported in this trial have major implications for interpretation of past and current clinical trials, and the design of future trials. This is the first trial in which IFN-gamma has been shown to have significant effects on the T-cell compartment of the immune system.
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PMID:Immunomodulatory function of interferon-gamma in patients with metastatic melanoma: results of a phase II-B trial in subjects with metastatic melanoma, ECOG study E 4987. Eastern Cooperative Oncology Group. 908 87

The effects of quercetin (4%) on UVB-induced carcinogenesis and immunosuppression were studied in hairless SKH-1 mice exposed daily to suberythemal UVB for 12/13 and 16/17 weeks. Macroscopic and microscopic examinations showed that quercetin did not affect the onset and growth of UVB-induced non-melanoma skin tumors. Quercetin prevented the UV-induced suppression of the contact hypersensitivity (CHS) and the reduction of the percentage of CD8-positive cells in spleen and lymph nodes. Other immunological parameters were not affected. Thus, the results indicate that oral intake of a high dose of quercetin does not prevent UVB-induced carcinogenesis, although it restores the skin-associated CHS response.
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PMID:The effect of oral quercetin on UVB-induced tumor growth and local immunosuppression in SKH-1. 910 88

Ultraviolet is thought to induce skin tumors by its dual activity as a mutagenic agent and a suppressor of cell-mediated immunity. In the present study the effects of quercetin, a flavonoid-containing compound, on carcinogenesis and immunosuppression were studied in SKH hairless mice exposed to suberythemal doses of UV for up to 17 weeks. It was found that quercetin did not affect the onset or growth of non-melanoma skin tumors resulting from UV exposure. In contrast, it prevented the suppression in contact hypersensitivity (CHS) to picryl chloride induced by UV. The mechanism of this prevention might be explained by the observation that the decreased number of epidermal Langerhans' cells is partly prevented by the quercetin. Quercetin did not alter the effects of UV in increasing numbers of spleen and lymph node cells, only partly in decreasing the CD8-positive cells in spleen cell populations and decreasing the lymphoproliferative response of spleen cells to the mitogens concanavalin A and phytohemagglutinin. Thus oral quercetin did not prevent UV-induced carcinogenesis although it restored the skin-associated CHS response probably by protecting the antigen-presenting cells in the skin.
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PMID:Quercetin prevents UV-induced local immunosuppression, but does not affect UV-induced tumor growth in SKH-1 hairless mice. 911 52

To elucidate the role of NK1.1+ T cells in the antitumor immune response, we established cloned NK1.1+ T cell lines from tumor-infiltrating lymphocytes (TIL) of B16 melanoma, and examined their mode of action in generating antitumor effector T cells both in vitro and in vivo. An NK1.1+ T cell clone (TM4.2) was phenotypically CD3+ TCR-alphabeta+ CD4- CD8- NK1.1+, and CD28+. The TM4.2 cells suppressed the in vitro generation of anti-B16 melanoma CTLs, but not the effector function of CTLs. The results using a transwell membrane suggested that their suppressive activity was mediated by both soluble factors and a direct cell to cell interaction. As for the soluble factors, the suppressive activity of the culture supernatant of TM4.2 cells was neutralized by anti-TGF-beta mAb, and the TM4.2 cells actually produced a considerable amount of TGF-beta. On the other hand, the TM4.2 cells showed a high level of cytolytic activity against B cell blasts and CD80-transfected P815, and such cytolytic activity was reduced by the addition of anti-CD80 mAb. In addition, NK1.1+ T cells in the freshly isolated TIL were revealed to express CD28. Furthermore, the TM4.2 cells suppressed the in vitro generation of anti-allo CTLs irrespective of the MHC haplotype. Finally, the TM4.2 cells suppressed the in vivo antitumor immune response. Collectively, these findings demonstrate that NK1.1+ T cells in TIL show immunosuppressive activity in the antitumor immune response through the production of TGF-beta and the preferential cytolysis of B7-expressing cells.
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PMID:Immunosuppressive activity of cloned natural killer (NK1.1+) T cells established from murine tumor-infiltrating lymphocytes. 914

Mice immunized with heat shock proteins (hsps) isolated from mouse tumor cells (donor cells) produce CD8 cytotoxic T lymphocytes (CTL) that recognize donor cell peptides in association with the major histocompatibility complex (MHC) class I proteins of the responding mouse. The CTL are induced apparently because peptides noncovalently associated with the isolated hsp molecules can enter the MHC class I antigen processing pathway of professional antigen-presenting cells. Using a recombinant heat shock fusion protein with a large fragment of ovalbumin covalently linked to mycobacterial hsp70, we show here that when the soluble fusion protein was injected without adjuvant into H-2b mice, CTL were produced that recognized an ovalbumin-derived peptide, SIINFEKL, in association with Kb. The peptide is known to arise from natural processing of ovalbumin in H-2b mouse cells, and CTL from the ovalbumin-hsp70-immunized mice and a highly effective CTL clone (4G3) raised against ovalbumin-expressing EL4 tumor cells (EG7-OVA) were equally effective in terms of the concentration of SIINFEKL required for half-maximal lysis in a CTL assay. The mice were also protected against lethal challenge with ovalbumin-expressing melanoma tumor cells. Because large protein fragments or whole proteins serving as fusion partners can be cleaved into short peptides in the MHC class I processing pathway, hsp fusion proteins of the type described here are promising candidates for vaccines aimed at eliciting CD8 CTL in populations of MHC-disparate individuals.
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PMID:Heat shock fusion proteins as vehicles for antigen delivery into the major histocompatibility complex class I presentation pathway. 937 14

A critical requirement for cancer vaccines is that they stimulate CD8+ T cell responses. In this study, we tested the ability of a polyvalent melanoma vaccine to induce CD8+ T cell responses to the melanoma associated antigens MAGE-3 and Melan A/MART-1. Fifteen HLA-A2+ patients with resected malignant melanoma were immunized with the vaccine s.c. every 2-3 weeks. CD8+ T cells in peripheral blood reacting to HLA-A2 restricted epitopes on MAGE-3 (FLWGPRALV) and Melan A/MART-1/(AAGIGILTV) were quantitated using a filter spot assay at baseline and following 4 immunizations. Vaccine immunization induced CD8+ T cells reacting to one or both of these peptides in 9 of the 15 (60%) patients. These cells were CD8+ and HLA-A2 restricted, as reactivity was abrogated by monoclonal antibodies (MAbs) to CD8 and class I HLA, but not by anti-CD4. All responding patients remained recurrence-free for at least 12 months (median 15 months, range 12 to >21 months), whereas melanoma recurred within 3-5 months in non-responders. The differences in outcome were unrelated to differences in disease severity or overall immunological competence between responders and non-responders. Our results demonstrate directly that MAGE-3 and Melan A/MART-1 can stimulate CD8+ T cell responses in humans, and suggest that these responses are protective and surrogate markers of vaccine efficacy.
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PMID:Stimulation of CD8+ T cell responses to MAGE-3 and Melan A/MART-1 by immunization to a polyvalent melanoma vaccine. 937 60

This study was designed to assess whether transfer of the interleukin-2 (IL-2) gene into human tumor cells could generate cytotoxic T lymphocytes (CTL) directed specifically against the autologous tumor. Two HLA class I+ melanoma cell lines, one (TOM) A2+ and the other (CLB-M) A2-, obtained from living patients were transduced with the IL-2 gene. The patients' peripheral blood lymphocytes (PBL) were incubated with irradiated IL-2 gene-transduced autologous tumor cells for up to four weeks. After seven days, PBL from both patients showed non-specific cytotoxic activity against the K562 cell line. When the co-culture incubation time was prolonged to 28 days, PBL from patient TOM (A2+) developed a lytic activity directed specifically against the autologous tumor cells. In contrast, after 28 days of incubation, PBL from CLB-M (A2-) displayed only non-specific cytotoxic activity. Inhibition experiments demonstrated that the specific lytic function observed with TOM cells transduced with the IL-2 gene could be reversed following incubation with monoclonal antibodies directed against HLA class I and CD8. The evidence that K562 cells were incapable of blocking the PBL killing capacity in a cold-target inhibition assay further confirmed that engineered TOM cells induced the generation of specific CTL. This study indicates that retroviral vector mediated transfer of the IL-2 gene into human melanoma cell lines can lead to the amplification of the autologous cytotoxic compartment and to the generation of specific antitumor CTL, and that the A2 allele may play an important role in the process of tumor recognition.
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PMID:IL-2 gene-transduced human HLA-A2 melanoma cells can generate a specific antitumor cytotoxic T-lymphocyte response. 938 64


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