Specialized dendritic cells induce tumor-promoting IL-10 + IL-17 + FoxP3 neg 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-HernandezJoshua Leinwand, Emma Kurz, Juan A.Kochen Rossi, Ankita Mishra, Miguel Liria, Gustavo Sanchez, Jyoti Panta, P’ng Loke, Berk Aykut, George Miller

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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 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.

Original languageEnglish
Article number1424
JournalNature Communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
Cell sorting/flow cytometry technologies were provided by NYU Langone’s Cytometry and Cell Sorting Laboratory, which is supported in part by grant P30CA016087 from the National Institutes of Health/National Cancer Institute. The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer. gov/tcga.

Publisher Copyright:
© 2019, The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • General
  • Physics and Astronomy (all)

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