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

• Published in: Nature communications Vol. 10; no. 1; p. 1424
• Main Authors: Barilla, Rocky M, Diskin, Brian, Caso, Raul Caso, Lee, Ki Buom, Mohan, Navyatha, Buttar, Chandan, Adam, Salma, Sekendiz, Zennur, Wang, Junjie, Salas, Ruben D, Cassini, Marcelo F, Karlen, Jason, Sundberg, Belen, Akbar, Hashem, Levchenko, Dmitry, Gakhal, Inderdeep, Gutierrez, Johana, Wang, Wei, Hundeyin, Mautin, Torres-Hernandez, Alejandro, Leinwand, Joshua, Kurz, Emma, Rossi, Juan A Kochen, Mishra, Ankita, Liria, Miguel, Sanchez, Gustavo, Panta, Jyoti, Loke, P'ng, Aykut, Berk, Miller, George
• Format: Journal Article
• Language: English
• Published: England 29.03.2019
• Subjects: 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
• ISSN: 2041-1723

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