Immunomodulatory impact of interferon-alpha in combination with chemoradiation of pancreatic adenocarcinoma (CapRI)

Background: Data from a phase II trial combining chemoradiotherapy with interferon-alpha (IFN-alpha) (CapRI scheme) for adjuvant treatment of pancreatic carcinoma are very encouraging. Methods: Eight human ductal pancreatic carcinoma cell lines were treated with the CapRI scheme [5-fluorouracil (5-FU), Cisplatin, IFN-a and radiation]. Natural killer (NK) and T cells preincubated with IFN-alpha were tested in cytotoxicity assays against these cell lines and the mechanism of cell lysis was investigated. The induction of the immunoproteasome in tumour cells after IFN-alpha stimulation was analysed by immunoblot and RTPCR. Results: IFN-alpha activated NK cells and increased their cytotoxicity. This cytotoxicity was mediated as well by Fas- induced apoptosis as by perforin release. Pre-treatment of tumour cells with 5-FU and combinations showed a significant increase in the susceptibility of tumour cells against NK cells. Treatment of tumour cells with IFN-alpha induced a switch to the immunoproteasome and enhanced their vulnerability to T cells. This is the first description of this phenomenon in pancreatic carcinoma cells with implications for their immunogenicity. Discussion: IFN-alpha activates NK cells against pancreatic carcinoma cells and 5-FU treatment makes tumour cells more susceptible. Furthermore, IFN-alpha induces the immunoproteasome with impact on the immunogenicity of pancreatic carcinoma cells. These mechanisms may be responsible for the improved clinical outcome of CapRI.