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Tumor-Derived MUC1 Mucins Interact with Differentiating Monocytes and Induce IL-10^highIL-12^low Regulatory Dendritic Cell¹

Paolo Monti^*, Biagio Eugenio Leone, Alessandro Zerbi^*, Gianpaolo Balzano^*, Silvia Cainarca, Valeria Sordi, Marina Pontillo^*, Alessia Mercalli, Valerio Di Carlo^*, Paola Allavena and Lorenzo Piemonti^2,*,

^* Laboratory of Experimental Surgery, Surgical Department, and Telethon-Juvenile Diabetes Research Foundation Center for Cell Replacement, San Raffaele Scientific Institute, University of Milan Bicocca, and Department of Immunology and Cell Biology, "Mario Negri" Institute, Milan, Italy

Dendritic cells (DC) initiate immunity by the activation of naive T cells and control immunity through their ability to induce unresponsiveness of lymphocytes by mechanisms that include deletion and induction of regulatory cells. An inadequate presentation to T cells by tumor-induced "regulatory" DC, among several mechanisms, can explain tolerance to tumor-associated Ags. In this study, we show that tumor-derived mucin profoundly affects the cytokine repertoire of monocyte-derived DC and switch them into IL-10^highIL-12^low regulatory APCs with a limited capacity to trigger protective Th1 responses. In fact, DC cocultured with pancreatic tumor cell lines in a Transwell system did not reach full maturation, had low immunostimulatory functions, did not produce IL-12, and released high levels of IL-10. The involvement of known tumor-derived immune-suppressive factors (e.g., vascular endothelial growth factor, TGF-, IL-6, and IL-10) was considered and excluded. We provide evidence that tumor-derived MUC1 mucins are responsible for the impaired DC maturation and function. DC obtained in the presence of tumor microenvironment preferentially polarized IL-4⁺ response. Moreover, T cells primed by these regulatory DC became anergic and behaved as suppressor/regulatory cells. These findings identify mucin secretion as a novel mechanism of tumor escape from immune surveillance and provide the basis for the generation of potentially tolerogenic DC.

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