Tumor-derived MUC1 mucins interact with differentiating monocytes and induce IL-10highIL-12low regulatory dendritic cell.
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(high)IL-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-beta, 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.
Monti
Paolo
P
Laboratory of Experimental Surgery, Surgical Department, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy.
Leone
Biagio Eugenio
BE
Zerbi
Alessandro
A
Balzano
Gianpaolo
G
Cainarca
Silvia
S
Sordi
Valeria
V
Pontillo
Marina
M
Mercalli
Alessia
A
Di Carlo
Valerio
V
Allavena
Paola
P
Piemonti
Lorenzo
L
D000938:Antigen-Presenting Cells / Q000276:immunology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D017635:Clonal Anergy; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D009000:Monocytes / Q000166:cytology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000473:pathology
D008565:Membrane Proteins; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4