Production of IL‐10 by melanoma cells: Examination of its role in immunosuppression mediated by melanoma

Chen, Qiyuan; Daniel, Vincent C.; Maher, Darryl; Hersey, Peter

doi:10.1002/ijc.2910560524

Cited by 224 publications

(117 citation statements)

References 23 publications

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“…DC of cancer patients exhibit dysfunction as a result of tumor cells secreting immunosuppressive cytokines such as transforming growth factor g (TGF-g ) [33], vascular endothelial growth factor (VEGF) [34], and IL-10 [35]. A promising means of eliciting tumor-specific antigen presentation to the immune system is to provide optimal DC to induce a Th1 response.…”

Section: Discussionmentioning

confidence: 99%

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

Liu

Akasaki

et al. 2004

Eur J Immunol

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RNA interference technology has been used to modulate dendritic cell (DC) function by targeting the expression of genes such as IL-12 and NF-kB. In this paper, we demonstrate that transfection of DC with IL-10-specific double strands of small interference RNA (siRNA) resulted in potent suppression of IL-10 gene expression without inducing DC apoptosis or blocking DC maturation. Inhibition of IL-10 by siRNA was accompanied by increased CD40 expression and IL-12 production after maturation, which endowed DC with the ability to significantly enhance allogeneic T cell proliferation. IL-10 siRNA transfection did not affect MHC class II, CD86, CD83, or CD54 expression in mature DC. To further test the ability of IL-10 siRNA-treated DC to induce a T cell response, naive CD4 T cells were stimulated by autologous DC pulsed with KLH. The results indicated that IL-10 siRNA-transfected DC enhanced Th1 responses by increasing IFN-+ and decreasing IL-4 production. These findings suggest the potential for a novel immunotherapeutic strategy of using IL-10 siRNAtransfected antigen-presenting cells as vaccine delivery agents to boost the Th1 response against pathogens and tumors that are controlled by Th1 immunity.

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Section: Discussionmentioning

confidence: 99%

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

Liu

Akasaki

et al. 2004

Eur J Immunol

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“…7,9 -11 IL-10 appears to be important in different types of human malignancy. [12][13][14][15][16][17][18] When the expression of IL-10 was evaluated in both the normal and abnormal cervix, it was shown that the severity of squamous intraepithelial lesions correlated with the increased expression of IL-10. The increased level of this immunomodulatory cytokine is localised to the transformation zone.…”

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confidence: 99%

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production

et al. 2001

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The purpose of our prospective, case-controlled study was to investigate the hypothesis that women who are genetically programmed to produce high or medium levels of IL-10 were more likely to develop cancer of the uterine cervix than individuals genetically predisposed to low IL-10 production. The population was recruited from patients attending gynecological clinics at 2 hospitals in Harare, Zimbabwe. Laboratory tests were performed in the Departments of Immunology, Chemical Pathology and Medical Microbiology, Medical School, University of Zimbabwe, and simultaneously at the Department of Biological Sciences, University of Manchester, United Kingdom. Included in our study were 77 women with histologically proven cancer of the uterine cervix and 69 age-and parity-matched healthy women. All of the patients and healthy controls were from the Shona ethnic group that inhabits northern Zimbabwe. DNA was purified from cervical cytobrush samples obtained from women with cervical cancer. Control DNA was extracted from urine or peripheral blood samples from the healthy women. The Qiagen DNA extraction kit was used. Detection of allele A and/or G at ؊1082 in the promoter region of the IL-10 gene was carried out using the ARMS-PCR technique. Polymorphism in the amplified products was detected by gel electrophoresis in the presence of ethidium bromide and were bands visualized under UV light. The data comprise 77 women who developed invasive cervical cancer and 69 healthy women matched for age and parity. Patients with cancer were significantly (p ‫؍‬ 0.001) more likely to be predisposed to produce higher (A/G) levels of IL-10. The genotype encoding for high (G/G) production of IL-10 was only observed in one cancer patient. The prevalence of low producers of IL-10 in the cancer group was significantly lower than in the healthy women. There were no high producers amongst the healthy women. These data suggest that the genetically acquired ability to produce higher levels of IL-10 may be a significant factor in the development of cervical cancer.

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“…The analysis of the cytokine spectrum displayed by melanoma cells (Becker et al, 1994;Chen et al 1994;Mattei et al, 1994;Dummer and Boni, 1995;Kruger-Krasagakes et al, 1995) revealed that melanoma cells transcribe and secrete IL-10. IL-10 is a cytokine with a variety of effects, including inhibition of monocyte major histocompatibility complex (MHC) class II-dependent antigen presentation, THI cytokine production and inhibition of T-cell proliferation (Howard and O'Garra, 1992;deWaal Malefyt et al, 1993;Becker et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Immune stimulatory potential of B7.1 and B7.2 retrovirally transduced melanoma cells: suppression by interleukin 10

Dummer

Yue²,

Pavlovic³

et al. 1998

Br J Cancer

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Summary The immunostimulatory capacities of B7.1-and B7.2-expressing melanoma cells were investigated. A365, 960306 and 950504 melanomas, established from nodular melanoma lesions, were retrovirally transduced. Irradiated B7-, B7.1 + and B7.2+ melanoma cells were co-cultured with autologous or allogeneic peripheral blood mononuclear cells (PBMCs). Proliferation was assessed by [3H]thymidine uptake. mRNA encoding for interleukin 2 (IL-2), IL-4, IL-10 and interferon gamma (IFN-y) was determined. IFN-y, IL-2, IL-4 and IL-10 secretion were quantitated by ELISA. B7.1+ and B7.2+ melanomas induced proliferation of PBMCs and mRNA for IL-2 and IFN-'y. After co-incubation of transduced melanoma cells with PBMCs, high levels of IL-10 were detectable in the supernatant. The presence of neutralizing anti-IL-10 antibodies resulted in enhanced proliferation and IL-2 and IFN-y secretion. Our data indicate that B7.1-and B7.2-transduced melanoma cells trigger lymphocytic proliferation with transcription of IL-10, IL-2 and IFN-y. Blocking of IL-10 augments these effects. Gene therapy protocols using tumour cells as a vaccine have to consider the adverse effects of IL-10.Keywords: melanoma; gene therapy; retroviral gene transfer; B7.1 (CD80); B7.2 (CD86); transduction; T-cell response; interleukin 2; interleukin 4; interleukin 10; interferon gamma Melanoma is an antigenic tumour (Bystryn, 1989). Several proteins have been identified that are presented as peptides in the grove of the HLA-I complex. These proteins include members of the MAGE family (Zakut et al, 1993), gp 100 (Bakker et al, 1994) or tyrosinase .Although melanoma presents various specific antigens associated with HLA-I, it does not induce an immune response, which results in an elimination of the malignant cells. It is speculated that melanoma cells induce tolerance instead of activation by presenting antigens without the respective co-stimulatory signals (Becker et al, 1993a). These co-stimulatory signals can be provided by B7. 1 (CD80) or B7.2 (CD86), two molecules capable of delivering co-stimulatory signals to T cells via CD 28 (Becker et al, 1993a;Freeman et al, 1991Freeman et al, , 1993Guinan et al, 1994).Thus, the immunogenicity of tumour cells is increased if the cells are transfected with human B7.1 (Dohring et al, 1994).Expression of the co-stimulatory ligand B7 on melanoma cells has been shown to induce the rejection of a murine melanoma in vivo (Townsend and Allison, 1993). In addition, treatment of mice bearing an 8-day established melanoma by intraperitoneal injection of B7+ tumour cells resulted in complete tumour regression and cure (Li et al, 1994). In human melanomas, B7.1 expression was found only in regressing lesions (Denfeld et al, 1995). Consequently, there are human gene therapy protocols for melanoma that apply melanoma cells genetically engineered to express B7.1 (Fenton et al, 1995 We analysed the immunostimulatory potential of a B7.1-and B7.2-transduced human melanoma cell line. We showed that B7. 1-and B7.2-transduced melanoma cells induc...

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Production of IL‐10 by melanoma cells: Examination of its role in immunosuppression mediated by melanoma

Cited by 224 publications

References 23 publications

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

Small interference RNA modulation of IL‐10 in human monocyte‐derived dendritic cells enhances the Th1 response

Cancer of the uterine cervix may be significantly associated with a gene polymorphism coding for increased IL-10 production

Immune stimulatory potential of B7.1 and B7.2 retrovirally transduced melanoma cells: suppression by interleukin 10

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