Low-dose interferon-γ-producing human neuroblastoma cells show reduced proliferation and delayed tumorigenicity

Interferon-γ (IFN-γ) directs T helper-1 cell differentiation and mediates antitumour effects in preclinical models. However, high-dose IFN-γ is toxic in vivo, and IFN-γ-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-γ gene and selected on the grounds of the low concentrations of IFN-γ produced. In both IFN-γ-transfected cell lines, autocrine and paracrine activation of IFN-γ-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-γ cells showed a significantly delayed tumorigenicity in nude mice as compared to parental cells. ACN/IFN-γ 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-γ 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-γ in syngeneic tumour-bearing hosts.