title: High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients.
abstract: Pancreatic cancer is characterized by aggressive growth and treatment resistance. New approaches include immunotherapeutic strategies but the type and extent of spontaneous immune responses against tumor antigens remains unclear. A dominance of TH2 cytokines in patients' sera reported previously suggests systemic tumor-induced immunosuppression, potentially inhibiting the induction of tumor-reactive T cells. We characterized the localization, frequencies, and functional potential of spontaneously induced memory T cells specific for individual tumor antigens or the tumor-associated antigen mucin-1 in the peripheral blood and bone marrow of 41 pancreatic cancer patients. We found high numbers of tumor-reactive T cells in all bone marrow samples and in 50% of the blood samples. These cells secreted the TH1 cytokine IFN-gamma rather than TH2 cytokines upon stimulation with tumor antigens. Although consistently induced during pancreatic cancer, T cells specific for pancreatic antigens were not detected during chronic pancreatitis, suggesting that their evaluation may be of diagnostic use in both diseases. Freshly isolated T cells from cancer patients recognized autologous tumor cells and rejected them in vitro and in a xenotransplant model in vivo, suggesting their therapeutic potential. Thus, tumor antigen-specific T cell responses occur regularly during pancreatic cancer disease and lead to enrichment of tumor cell-reactive memory T cells in the bone marrow. The bone marrow can therefore be considered an important organ for antitumor immune responses in pancreatic cancer.
authors.affiliation: Department of General Surgery, the University Hospital of Heidelberg, Germany.
authors.forename: Friedrich H
authors.initials: FH
authors.lastname: Schmitz-Winnenthal
authors.forename: Christine
authors.initials: C
authors.lastname: Volk
authors.forename: Kaspar
authors.initials: K
authors.lastname: Z'graggen
authors.forename: Luis
authors.initials: L
authors.lastname: Galindo
authors.forename: Daniel
authors.initials: D
authors.lastname: Nummer
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Ziouta
authors.forename: Marianna
authors.initials: M
authors.lastname: Bucur
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Volker
authors.initials: V
authors.lastname: Schirrmacher
authors.forename: Markus W
authors.initials: MW
authors.lastname: Büchler
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000941:Antigens / Q000276:immunology; D000951:Antigens, Neoplasm; D001854:Bone Marrow Cells / Q000276:immunology*; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D006023:Glycoproteins / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D018396:Mucin-1; D009077:Mucins / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000097:blood / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000941:Antigens; D000951:Antigens, Neoplasm; D006023:Glycoproteins; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; D007371:Interferon-gamma