Interferon-alpha enhances antitumor effect of chemotherapy in an orthotopic mouse model for pancreatic adenocarcinoma.
Data from a phase 2 trial combining chemoradiotherapy with interferon (IFN)-alpha (CapRI scheme) for adjuvant treatment of pancreatic carcinoma are very encouraging. Here, we try to evaluate the effect of IFN-alpha in this combined treatment scheme. Mice were inoculated with syngeneic cells in the pancreas. After 5 days animals were treated with 5-fluorouracil (5-FU), cisplatin (CDDP), radiation, and IFN-alpha. Tumor growth and immune responses were determined and adoptive cell transfer experiments performed. The impact of IFN-alpha treatment on leukocyte-endothelium interactions was assessed by intravital microscopy. Addition of IFN-alpha to chemotherapy had a significant life-prolonging effect. Regimens including IFN-alpha showed a clear trend toward less metastases than monotherapy. T cells and dendritic cells infiltrated tumors significantly more in 5-FU+IFN-alpha animals and these T cells secreted IFN-gamma tumor specifically. Antitumor response could be transferred by injection of mononuclear cells from 5-FU+IFN-alpha-treated mice into treatment-naive animals. The transferred cells homed to the tumors and proliferated there. Furthermore, significant more leukocytes were rolling and sticking to the endothelium. IFN-alpha significantly improves chemotherapy. This is mainly mediated by immunomodulation with improved adherence of leukocytes to the endothelium, infiltration, and lysis. Although IFN-alpha acts unspecifically an additional specific immune response could be demonstrated.
Zhu
Yifan
Y
Department of Surgery, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
Tibensky
Igor
I
Schmidt
Jan
J
Ryschich
Eduard
E
Märten
Angela
A
D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D005472:Fluorouracil / Q000008:administration & dosage; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000008:administration & dosage*; D008113:Liver Neoplasms / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D011878:Radiotherapy; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
D000276:Adjuvants, Immunologic; D016207:Cytokines; D016898:Interferon-alpha; D002945:Cisplatin; D005472:Fluorouracil