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-Hernandez

Joshua 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

71 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 - 1 Dec 2019
Externally published	Yes

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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

@article{9fbaad5c51784a5798220e8969854f1a,

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 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.",

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",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09416-2",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

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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

TY - JOUR

T1 - Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3 neg regulatory CD4+ T cells in pancreatic carcinoma

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 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.

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 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.

UR - https://www.scopus.com/pages/publications/85063719241

U2 - 10.1038/s41467-019-09416-2

DO - 10.1038/s41467-019-09416-2

M3 - Article

C2 - 30926808

AN - SCOPUS:85063719241

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1424

ER -

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

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