Different effects of interferon-alpha on melanoma cell lines: a study on telomerase reverse transcriptase, telomerase activity and apoptosis

Maellaro, Emilia; Pacenti, Lorenzo; Bello, Barbara Del; Valentini, Melissa; Mangiavacchi, Paola; Felice, Claudio De; Rubegni, Pietro; Luzi, Pietro; Miracco, Clelia

doi:10.1046/j.1365-2133.2003.05301.x

Cited by 24 publications

(15 citation statements)

References 40 publications

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“…In tumor models, low endogenous levels of IFN-α promoted anti-tumor activity of CD8+ T cells (21), while exogenous IFN-α enhanced the efficacy of GM-CSF-secreting whole-cell melanoma vaccine (22), and IFN-α-secreting colorectal tumor cells promoted expansion and survival of tumor-specific CTL (23). While IFN-α is believed to have a direct cytostatic/cytocidal effect on human melanoma(24-26), there is strong evidence that it also acts through an immune-mediated mechanism. A recent large study showed that development of autoimmune phenomena in melanoma patients after IFN-α treatment strongly correlated with improved survival (27).…”

Section: Introductionmentioning

confidence: 99%

IFN-α Enhances Peptide Vaccine-Induced CD8+ T Cell Numbers, Effector Function, and Antitumor Activity

Sikora

Jaffarzad

Hailemichael

et al. 2009

The Journal of Immunology

101

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Type I IFNs, including IFN-α, enhance Ag presentation and promote the expansion, survival, and effector function of CD8+ CTL during viral infection. Because these are ideal characteristics for a vaccine adjuvant, we examined the efficacy and mechanism of exogenous IFN-α as an adjuvant for antimelanoma peptide vaccination. We studied the expansion of pmel-1 transgenic CD8+ T cells specific for the gp100 melanocyte differentiation Ag after vaccination of mice with gp10025–33 peptide in IFA. IFN-α synergized with peptide vaccination in a dose-dependent manner by boosting relative and absolute numbers of gp100-specific T cells that suppressed B16 melanoma growth. IFN-α dramatically increased the accumulation of gp100-specific, IFN-γ-secreting, CD8+ T cells in the tumor through reduced apoptosis and enhanced proliferation of Ag-specific CD8+ T cells. IFN-α treatment also greatly increased the long-term maintenance of pmel-1 CD8+ T cells with an effector memory phenotype, a process that required expression of IFN-α receptor on the T cells and IL-15 in the host. These results demonstrate the efficacy of IFN-α as an adjuvant for peptide vaccination, give insight into its mechanism of action, and provide a rationale for clinical trials in which vaccination is combined with standard-of-care IFN-α therapy for melanoma.

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Section: Introductionmentioning

confidence: 99%

IFN-α Enhances Peptide Vaccine-Induced CD8+ T Cell Numbers, Effector Function, and Antitumor Activity

Sikora

Jaffarzad

Hailemichael

et al. 2009

The Journal of Immunology

101

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“…The IFN-α-receptor is expressed on melanoma tumor cells as well as on immune effectors and mediates many of its effects via activation of the Janus kinase (Jak)-signal transducers and activators of transcription (STAT) pathway. IFN-α exerts direct anti-proliferative, pro-apoptotic, and anti-angiogenic effects on melanoma cells in culture and has distinct immunostimulatory effects that vary according to the immune subset under study (1–4). Unfortunately, the precise molecular targets of exogenously administered IFN-α are unknown.…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling Reveals Similarities between theIn vitroandIn vivoResponses of Immune Effector Cells to IFN-α

Zimmerer

Lesinski

Ruppert³

et al. 2008

Clinical Cancer Research

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Purpose: The precise molecular targets of IFN-a therapy in the context of malignant melanoma are unknown but seem to involve signal transducers and activators of transcription 1signal transduction within host immune effector cells. We hypothesized that the in vitro transcriptional response of patient peripheral blood mononuclear cells (PBMC) to IFN-a would be similar to the in vivo response to treatment with high-dose IFN-a. Experimental Design: The gene expression profiles of PBMCs and immune cell subsets treated in vitro with IFN-a were evaluated, as were PBMCs obtained from melanoma patients receiving adjuvant IFN-a. Results: Twenty-seven genes were up-regulated in PBMCs from normal donors after treatment with IFN-a in vitro for18 hours (>2-fold, P < 0.001). A subset of these genes (in addition to others) was significantly expressed in IFN-a^treated Tcells, natural killer cells, and monocytes. Analysis of gene expression within PBMCs from melanoma patients (n = 13) receiving high-dose IFN-a2b (20 MU/m 2 i.v.) revealed significant up-regulation (>2-fold) of 21genes (P < 0.001). Also, the gene expression profile of in vitro IFN-a^stimulated patient PBMCs was similar to that of PBMCs obtained from the same patient after IFN-a therapy. Conclusions: This report is the first to describe the transcriptional response of T cells, natural killer cells, and monocytes to IFN-a and characterize the transcriptional profiles of PBMCs from melanoma patients undergoing IFN-a immunotherapy. In addition, it was determined that microarray analysis of patient PBMCs after in vitro stimulation with IFN-a may be a useful predictor of the in vivo response of immune cells to IFN-a immunotherapy.Surgical treatment of early-stage malignant melanoma is frequently curative. However, the therapeutic options for patients with metastatic disease are limited. IFN-a has been used, both as an adjuvant after the surgical resection of high-risk lesions (lymph node metastases or primary tumor thickness, >4 mm) and in advanced disease setting. The IFN-a receptor is expressed on melanoma tumor cells, as well as on immune effectors, and mediates many of its effects via activation of the Janus kinase -signal transducers and activators of transcription (STAT) pathway. IFN-a exerts direct antiproliferative, proapoptotic, and antiangiogenic effects on melanoma cells in culture and has distinct immunostimulatory effects that vary according to the immune subset under study (1-4). Unfortunately, the precise molecular targets of exogenously given IFN-a are unknown. As a result, it is not currently possible to identify patients who would have a high likelihood of responding to this treatment.We have examined the role of the Janus kinase -STAT signaling pathway in a murine model of malignant melanoma using STAT1-deficient mice and STAT1-deficient melanoma cell lines. It was found that loss of STAT1 signal transduction within the host abrogated the antitumor effects of IFN-a (5). In contrast, the survival benefits associated with IFN-a administration w...

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“…Cells were routinely harvested by phosphatebuffered saline (PBS)-ethylene diamine tetra acetic acid (EDTA) (0.2 g/l) and reseeded before reaching confluence. In selected experiments, we used four different unselected cell lines, also derived from metastases of human melanomas: Me665/2/60, HT-144 and SK-Mel-28, cultured in standard conditions, as described previously (Maellaro et al, 2003). Cells were treated for different experimental times with cisplatin CDDP (Sigma) at the concentration of 1 mg/ml, unless otherwise stated, at the constant ratio of 20 nmol/10 6 cells.…”

Section: Cell Culture and Treatmentsmentioning

confidence: 99%

Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status

et al. 2006

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Different effects of interferon-alpha on melanoma cell lines: a study on telomerase reverse transcriptase, telomerase activity and apoptosis

Cited by 24 publications

References 40 publications

IFN-α Enhances Peptide Vaccine-Induced CD8+ T Cell Numbers, Effector Function, and Antitumor Activity

IFN-α Enhances Peptide Vaccine-Induced CD8+ T Cell Numbers, Effector Function, and Antitumor Activity

Gene Expression Profiling Reveals Similarities between theIn vitroandIn vivoResponses of Immune Effector Cells to IFN-α

Cross-talk between calpain and caspase-3/-7 in cisplatin-induced apoptosis of melanoma cells: a major role of calpain inhibition in cell death protection and p53 status

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