title: Genetically induced pancreatic adenocarcinoma is highly immunogenic and causes spontaneous tumor-specific immune responses.
abstract: Treatment options for pancreatic cancer are limited and often ineffective. Immunotherapeutic approaches are one possible option that needs to be evaluated in appropriate animal models. The aim of the present study was to analyze tumor-specific immune responses in a mouse model of pancreatic cancer, which mimics the human disease closely. C57BL/6 EL-TGF-alpha x Trp53-/- mice, which develop spontaneous ductal pancreatic carcinoma, were generated. EL-TGF-alpha x Trp53-/- mice developed spontaneous pancreatic tumors with pathomorphologic features close to the human disease. Tumor-specific CD8+ T-cell responses and IgG responses were analyzed in EL-TGF-alpha x Trp53-/- mice during tumor development and compared with mice with s.c. growing pancreatic tumors. In contrast to spontaneous pancreatic tumors, cell lines generated from these tumors were rejected after s.c. injection into wild-type mice but not in nude or RAG knockout mice. Direct comparison of spontaneous and s.c. injected tumors revealed an impaired infiltration of CD8+ T cells in spontaneous pancreatic tumors, which was also evident after adoptive transfer of tumor-specific T cells. Intratumoral cytokine secretion of tumor necrosis factor-alpha, IFN-gamma, IL-6, and MCP-1 was lower in spontaneous tumors as well as the number of adoptively transferred tumor-specific T cells. Our data provide clear evidence for tumor-specific immune responses in a genetic mouse model for pancreatic carcinoma. Comparative analysis of s.c. injected tumors and spontaneous tumors showed significant differences in tumor-specific immune responses, which will help in improving current immune-based cancer therapies against adenocarcinoma of the pancreas.
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Annette I
authors.initials: AI
authors.lastname: Garbe
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vermeer
authors.forename: Jaba
authors.initials: J
authors.lastname: Gamrekelashvili
authors.forename: Reinhard
authors.initials: R
authors.lastname: von Wasielewski
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Westendorf
authors.forename: Jan
authors.initials: J
authors.lastname: Buer
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Korangy
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D016207:Cytokines; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53