Specialized dendritic cells induce tumor-promoting IL-10(+)IL-17(+) FoxP3(neg) regulatory CD4(+) T cells in pancreatic carcinoma

The drivers and the specification of CD4(+) T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T(H)-program. Specifically, CD11b(+)CD103(−) DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3(neg) tumor-promoting IL-10(+)IL-17(+)IFNγ(+ )regulatory CD4(+) T cells. The balance between this distinctive T(H) program and canonical FoxP3(+ )T(REGS) is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T(H)-signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b(+)CD103(−) DC promote CD4(+) T cell tolerance in PDA which may underscore its resistance to immunotherapy.