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Published on: September 1, 2018
Low-dose interferon-gamma-producing human neuroblastoma cells show reduced proliferation and delayed tumorigenicity
1Laboratory of Oncology, Gaslini Institute, Largo Gaslini 5, 16148 Genoa, Italy.
Abstract:
Interferon-gamma (IFN-gamma) directs T helper-1 cell differentiation and mediates antitumour effects in preclinical models. However, high-dose IFN-gamma is toxic in vivo, and IFN-gamma-transfected neuroblastoma (NB) cells secreting high amounts of the cytokine may be lost due to cell apoptosis or differentiation. Two human NB cell lines (ACN and SK-N-BE2(c)) differing as to genetic and phenotypic features were transfected with the human IFN-gamma gene and selected on the grounds of the low concentrations of IFN-gamma produced. In both IFN-gamma-transfected cell lines, autocrine and paracrine activation of IFN-gamma-mediated pathways occurred, leading to markedly reduced proliferation rate, to increased expression of surface HLA and CD40 molecules and of functional TNF binding sites. ACN/IFN-gamma cells showed a significantly delayed tumorigenicity in nude mice as compared to parental cells. ACN/IFN-gamma tumours were smaller, with extensive necrotic area as a result of a damaged and defective microvascular network. In addition, a significant reduction in the proliferation index was observed. This is the first demonstration that IFN-gamma inhibits in vivo proliferation of NB cell by acting on the tumour cell itself. This effect adds to the immunoregulatory and antiangiogenic activities operated by IFN-gamma in syngeneic tumour-bearing hosts.
Insights
Interferon-gamma (IFN-gamma) gene transfer into neuroblastoma cells reduced tumor growth in mice. This study shows IFN-gamma directly inhibits neuroblastoma proliferation in vivo.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Interferon-gamma (IFN-gamma) has demonstrated preclinical antitumour effects but exhibits in vivo toxicity at high doses.
- IFN-gamma-transfected neuroblastoma (NB) cells may be lost due to apoptosis or differentiation, limiting therapeutic potential.
Purpose of the Study:
- To investigate the efficacy of low-dose IFN-gamma-transfected neuroblastoma cells in inhibiting tumour growth.
- To explore the direct effects of IFN-gamma on neuroblastoma cell proliferation and tumour microenvironment.
Main Methods:
- Two human neuroblastoma cell lines (ACN and SK-N-BE2(c)) were transfected with the human IFN-gamma gene.
- IFN-gamma-producing cells were selected for low cytokine concentrations.
- Tumorigenicity and tumour characteristics were assessed in nude mice models.
Main Results:
- IFN-gamma transfection led to autocrine and paracrine activation of IFN-gamma pathways, reducing proliferation and increasing HLA and CD40 expression.
- ACN/IFN-gamma cells exhibited significantly delayed tumorigenicity in nude mice.
- Tumours derived from ACN/IFN-gamma cells were smaller, showed increased necrosis, and had a defective microvascular network.
Conclusions:
- IFN-gamma directly inhibits neuroblastoma cell proliferation in vivo by acting on the tumour cells themselves.
- This study demonstrates a novel therapeutic strategy for neuroblastoma, leveraging IFN-gamma's direct antiproliferative, immunoregulatory, and antiangiogenic activities.
