High frequencies of functional tumor-reactive T cells in bone marrow and blood of pancreatic cancer patients.
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.
Schmitz-Winnenthal
Friedrich H
FH
Department of General Surgery, the University Hospital of Heidelberg, Germany.
Volk
Christine
C
Z'graggen
Kaspar
K
Galindo
Luis
L
Nummer
Daniel
D
Ziouta
Yvonne
Y
Bucur
Marianna
M
Weitz
Jürgen
J
Schirrmacher
Volker
V
Büchler
Markus W
MW
Beckhove
Philipp
P
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
D000941:Antigens; D000951:Antigens, Neoplasm; D006023:Glycoproteins; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; D007371:Interferon-gamma