Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells.
Ag presentation by dendritic cells (DC) is essential to effective antitumor T cell responses in cancer patients. Depending on their origin, maturation state, and the ambient cytokine milieu, DC can differentiate into distinct subpopulations, which preferentially either induce Th1 cell activation (CD11c+,CD123- myeloid DC (MDC)) or immunosuppressive T cell development (CD11c-,CD123+ plasmacytoid DC (PDC)). The present study was undertaken to characterize the effects of pancreatic carcinoma cell-derived cytokines on immature monocyte-derived DC (iMo-DC) in vitro and in vivo. Medium conditioned by human pancreatic carcinoma cells inhibited iMo-DC proliferation, expression of costimulatory molecules (CD80 and CD40) and of HLA-DR, and functional activity as assessed by MLR and IL-12p70 production. iMo-DC generated from pancreatic carcinoma patients in advanced stages of the disease similarly showed decreased levels of HLA-DR expression and reduced ability to stimulate MLR in response to CD40L and IFN-gamma. Moreover, in tumor-patient peripheral blood, the ratio of MDC to PDC cells was lower than in healthy controls due to reduced numbers of MDC CD11c+ cells. Importantly, rather than a single cytokine, a combination of tumor-derived cytokines was responsible for these effects; these were primarily TGF-beta, IL-10, and IL-6, but not vascular endothelial growth factor. In summary, we have identified an array of pancreatic carcinoma-derived cytokines that cooperatively affect iMo-DC activation in a manner consistent with ineffective antitumor immune responses.
Bellone
Graziella
G
Department of Clinical Physiopathology, University of Turin, Italy. graziella.bellone@unito.it
Carbone
Anna
A
Smirne
Carlo
C
Scirelli
Tiziana
T
Buffolino
Alessandra
A
Novarino
Anna
A
Stacchini
Alessandra
A
Bertetto
Oscar
O
Palestro
Giorgio
G
Sorio
Claudio
C
Scarpa
Aldo
A
Emanuelli
Giorgio
G
Rodeck
Ulrich
U
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003470:Culture Media; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D003470:Culture Media; D016207:Cytokines; D012333:RNA, Messenger