title: 5-Fluorouracil and interferon-α immunochemotherapy enhances immunogenicity of murine pancreatic cancer through upregulation of NKG2D ligands and MHC class I.
abstract: Pancreatic cancer has the poorest prognosis of all gastrointestinal cancers, driving the need for new therapeutic approaches. Adjuvant 5-fluorouacil (5-FU) chemotherapy proved effective in increasing the survival of patients with resected tumors. Furthermore, the addition of interferon alpha (IFN-α) immunotherapy to 5-FU has shown encouraging clinical results. The aim of this study was to determine the relevance of different immune cell populations, namely natural killer (NK) cells, CD8 T cells, and dendritic cells, in the anticancer immune response mediated by the combination therapy using an orthotopic mouse model of pancreatic carcinoma and to get more insight into the underlying mechanisms of action. Depleting CD8 T cells, NK cells, or dendritic cells significantly reduced the anticancer effects mediated by the combination therapy. Tumors of mice treated with 5-FU+IFN-α harbored higher numbers of infiltrating NK cells in comparison with control mice. In addition, NK cells isolated from these mice showed enhanced cytotoxicity against Panc02 pancreatic cancer cells. Furthermore, 5-FU+IFN-α treatment increased the expression of major histocompatibility complex class I and NKG2D ligands on Panc02 cells that could be a potential key for enhancing the immunogenicity of tumors. Understanding how this combination therapy enhances the immunogenicity of pancreatic tumors in our model may provide potential predictive biomarkers. This will allow to evaluate the efficacy of this immunochemotherapy more effectively in future clinical trials and to identify patients who will benefit most from it.
authors.affiliation: University Hospital Heidelberg, AG Jäger, INF 460, 69120 Heidelberg, Germany. khallouf@stud.uni-heidelberg.de
authors.forename: Hadeel
authors.initials: H
authors.lastname: Khallouf
authors.forename: Angela
authors.initials: A
authors.lastname: Märten
authors.forename: Susanne
authors.initials: S
authors.lastname: Serba
authors.forename: Volker
authors.initials: V
authors.lastname: Teichgräber
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D005472:Fluorouracil / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006183:H-2 Antigens / Q000235:genetics / Q000378:metabolism*; D016898:Interferon-alpha / Q000008:administration & dosage; D007694:Killer Cells, Natural / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*
chemical_list: D006183:H-2 Antigens; D016898:Interferon-alpha; D055655:NK Cell Lectin-Like Receptor Subfamily K; D005472:Fluorouracil