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-Hernandez; Joshua Leinwand; Emma Kurz; Juan A.Kochen Rossi; Ankita Mishra; Miguel Liria; Gustavo Sanchez; Jyoti Panta; P’ng Loke; Berk Aykut; George Miller

doi:10.1038/s41467-019-09416-2

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 journal › Article › peer-review

65 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 language	English
Article number	1424
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09416-2
State	Published - Dec 1 2019

Bibliographical note

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

Funding

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.

Funders	Funder number
National Institutes of Health/National Cancer Institute
National Childhood Cancer Registry – National Cancer Institute	T32CA193111
Department of Psychiatry, Columbia University Irving Medical Center, New York, USA; New York State Psychiatric Institute, New York, USA	P30CA016087

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

Access to Document

10.1038/s41467-019-09416-2

Cite this

Barilla, R. M., Diskin, B., Caso, R. C., Lee, K. B., Mohan, N., Buttar, C., Adam, S., Sekendiz, Z., Wang, J., Salas, R. D., Cassini, M. F., Karlen, J., Sundberg, B., Akbar, H., Levchenko, D., Gakhal, I., Gutierrez, J., Wang, W., Hundeyin, M., ... Miller, G. (2019). Specialized dendritic cells induce tumor-promoting IL-10 ⁺ IL-17 ⁺ FoxP3 ^neg regulatory CD4 ⁺ T cells in pancreatic carcinoma Nature Communications, 10(1), Article 1424. https://doi.org/10.1038/s41467-019-09416-2

Barilla, Rocky M. ; Diskin, Brian ; Caso, Raul Caso et al. / Specialized dendritic cells induce tumor-promoting IL-10 ⁺ IL-17 ⁺ FoxP3 ^neg regulatory CD4 ⁺ T cells in pancreatic carcinoma In: Nature Communications. 2019 ; Vol. 10, No. 1.

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

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.",

author = "Barilla, \{Rocky M.\} and Brian Diskin and Caso, \{Raul Caso\} and Lee, \{Ki Buom\} and Navyatha Mohan and Chandan Buttar and Salma Adam and Zennur Sekendiz and Junjie Wang and Salas, \{Ruben D.\} and Cassini, \{Marcelo F.\} and Jason Karlen and Belen Sundberg and Hashem Akbar and Dmitry Levchenko and Inderdeep Gakhal and Johana Gutierrez and Wei Wang and Mautin Hundeyin and Alejandro Torres-Hernandez and Joshua Leinwand and Emma Kurz and Rossi, \{Juan A.Kochen\} and Ankita Mishra and Miguel Liria and Gustavo Sanchez and Jyoti Panta and P{\textquoteright}ng Loke and Berk Aykut and George Miller",

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Barilla, RM, Diskin, B, Caso, RC, Lee, KB, Mohan, N, Buttar, C, Adam, S, Sekendiz, Z, Wang, J, Salas, RD, Cassini, MF, Karlen, J, Sundberg, B, Akbar, H, Levchenko, D, Gakhal, I, Gutierrez, J, Wang, W, Hundeyin, M, Torres-Hernandez, A, Leinwand, J, Kurz, E, Rossi, JAK, Mishra, A, Liria, M, Sanchez, G, Panta, J, Loke, P, Aykut, B & Miller, G 2019, ' Specialized dendritic cells induce tumor-promoting IL-10 ⁺ IL-17 ⁺ FoxP3 ^neg regulatory CD4 ⁺ T cells in pancreatic carcinoma ', Nature Communications, vol. 10, no. 1, 1424. https://doi.org/10.1038/s41467-019-09416-2

Specialized dendritic cells induce tumor-promoting IL-10 ⁺ IL-17 ⁺ FoxP3 ^neg regulatory CD4 ⁺ T cells in pancreatic carcinoma . / Barilla, Rocky M.; Diskin, Brian; Caso, Raul Caso et al.
In: Nature Communications, Vol. 10, No. 1, 1424, 01.12.2019.

Research output: Contribution to journal › Article › peer-review

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AU - Barilla, Rocky M.

AU - Diskin, Brian

AU - Caso, Raul Caso

AU - Lee, Ki Buom

AU - Mohan, Navyatha

AU - Buttar, Chandan

AU - Adam, Salma

AU - Sekendiz, Zennur

AU - Wang, Junjie

AU - Salas, Ruben D.

AU - Cassini, Marcelo F.

AU - Karlen, Jason

AU - Sundberg, Belen

AU - Akbar, Hashem

AU - Levchenko, Dmitry

AU - Gakhal, Inderdeep

AU - Gutierrez, Johana

AU - Wang, Wei

AU - Hundeyin, Mautin

AU - Torres-Hernandez, Alejandro

AU - Leinwand, Joshua

AU - Kurz, Emma

AU - Rossi, Juan A.Kochen

AU - Mishra, Ankita

AU - Liria, Miguel

AU - Sanchez, Gustavo

AU - Panta, Jyoti

AU - Loke, P’ng

AU - Aykut, Berk

AU - Miller, George

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

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Barilla RM, Diskin B, Caso RC, Lee KB, Mohan N, Buttar C et al. Specialized dendritic cells induce tumor-promoting IL-10 ⁺ IL-17 ⁺ FoxP3 ^neg regulatory CD4 ⁺ T cells in pancreatic carcinoma Nature Communications. 2019 Dec 1;10(1):1424. doi: 10.1038/s41467-019-09416-2