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-alpha 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 RT-PCR.


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.


CONCLUSIONS
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.
Schmidt
Jan
J
Department of Surgery, University of Heidelberg, Im Neuenheimer Feld 350, 69120 Heidelberg, Germany.
Patrut
Emilia M
EM
Ma
Jianhua
J
Jäger
Dirk
D
Knaebel
Hanns-Peter
HP
Büchler
Markus W
MW
Märten
Angela
A
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D016898:Interferon-alpha / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology; D008214:Lymphocytes / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D016898:Interferon-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex