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Cooperative Induction of a Tolerogenic Dendritic Cell Phenotype by Cytokines Secreted by Pancreatic Carcinoma Cells¹

Graziella Bellone^2,*, Anna Carbone^*,, Carlo Smirne^*, Tiziana Scirelli^*, Alessandra Buffolino^*, Anna Novarino, Alessandra Stacchini^¶, Oscar Bertetto, Giorgio Palestro^¶, Claudio Sorio^||, Aldo Scarpa^||, Giorgio Emanuelli^*, and Ulrich Rodeck^#

^* Department of Clinical Physiopathology and Department of Biomedical Sciences and Human Oncology, University of Turin, Italy; Department of Gastroenterology and Clinical Nutrition, Department of Oncology, and ^¶ Department of Anatomic Pathology, San Giovanni Battista Hospital, Turin, Italy; ^|| Department of Pathology, University of Verona, Italy; and ^# Department of Dermatology, Thomas Jefferson University, Philadelphia, PA 19107

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-. 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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by research funds from Ministero Università dell’Istruzione, dell’Università e della Ricerca (Rome, Italy) (to G.E. and to A.S.), and in part by grants from the Piedmont Regional Government (Regione Piemonte, Italy) (to G.B.), Fondazione Cassa di Risparmio di Verona, Associazione Italiana Ricerca Cancro (Milan, Italy) (to A.S), and the National Institutes of Health (to U.R.). A.B. is the recipient of an award from the Piedmontese Regional Government. T.S. is the recipient of an award from the Fondazione Compagnia di San Paolo, Turin, Italy.

² Address correspondence and reprint requests to Dr. Graziella Bellone, Department of Clinical Physiopathology, Università di Torino, Via Genova, 3, 10126 Torino, Italy. E-mail address: graziella.bellone{at}unito.it

³ Abbreviations used in this paper: DC, dendritic cell; MDC, myeloid DC; PDC, plasmacytoid DC; Mo-DC, monocyte-derived DC; VEGF, vascular endothelial growth factor; iMo-DC, immature Mo-DC; MFI, mean fluorescence intensity; CM, conditioned medium; Ct, cycle threshold value; PI, propidium iodide; PB, peripheral blood.

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