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

Rocky M. Barilla, Brian Diskin, Raul Caso Caso, Ki Buom Lee, Navyatha Mohan, Chandan Buttar, Salma Adam, Zennur Sekendiz, Junjie Wang, Ruben D. Salas, Marcelo F. Cassini, Jason Karlen, Belen Sundberg, Hashem Akbar, Dmitry Levchenko, Inderdeep Gakhal, Johana Gutierrez, Wei Wang, Mautin Hundeyin, Alejandro Torres-Hernandez, Joshua Leinwand, Emma Kurz, Juan A. Kochen Rossi, Ankita Mishra, Miguel Liria, Gustavo Sanchez, Jyoti Panta, P’ng Loke, Berk Aykut and George Miller ()
Additional contact information
Rocky M. Barilla: New York University School of Medicine
Brian Diskin: New York University School of Medicine
Raul Caso Caso: New York University School of Medicine
Ki Buom Lee: New York University School of Medicine
Navyatha Mohan: New York University School of Medicine
Chandan Buttar: New York University School of Medicine
Salma Adam: New York University School of Medicine
Zennur Sekendiz: New York University School of Medicine
Junjie Wang: New York University School of Medicine
Ruben D. Salas: New York University School of Medicine
Marcelo F. Cassini: New York University School of Medicine
Jason Karlen: New York University School of Medicine
Belen Sundberg: New York University School of Medicine
Hashem Akbar: New York University School of Medicine
Dmitry Levchenko: New York University School of Medicine
Inderdeep Gakhal: New York University School of Medicine
Johana Gutierrez: New York University School of Medicine
Wei Wang: New York University School of Medicine
Mautin Hundeyin: New York University School of Medicine
Alejandro Torres-Hernandez: New York University School of Medicine
Joshua Leinwand: New York University School of Medicine
Emma Kurz: New York University School of Medicine
Juan A. Kochen Rossi: New York University School of Medicine
Ankita Mishra: New York University School of Medicine
Miguel Liria: New York University School of Medicine
Gustavo Sanchez: New York University School of Medicine
Jyoti Panta: New York University School of Medicine
P’ng Loke: New York University School of Medicine
Berk Aykut: New York University School of Medicine
George Miller: New York University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09416-2

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