Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma

Nat Commun. 2019 Mar 29;10(1):1424. doi: 10.1038/s41467-019-09416-2.

Abstract

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 TH-program. Specifically, CD11b+CD103- DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3neg tumor-promoting IL-10+IL-17+IFNγ+ regulatory CD4+ T cells. The balance between this distinctive TH program and canonical FoxP3+ TREGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This TH-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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Differentiation
  • Dendritic Cells / immunology*
  • Disease Progression
  • Forkhead Transcription Factors
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Interleukin-10 / metabolism*
  • Interleukin-17 / metabolism*
  • Lectins, C-Type / metabolism
  • Mice, Inbred C57BL
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Phenotype
  • Signal Transduction
  • T-Lymphocytes, Regulatory / immunology*
  • Th17 Cells / immunology
  • Toll-Like Receptor 2 / metabolism
  • Tretinoin / metabolism

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Interleukin-17
  • Lectins, C-Type
  • Toll-Like Receptor 2
  • dectin 1
  • Interleukin-10
  • Tretinoin