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.

Duke Scholars

Author Berk Aykut