γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Donnele Daley; Constantinos Pantelis Zambirinis; Lena Seifert; Neha Akkad; Navyatha Mohan; Gregor Werba; Rocky Barilla; Alejandro Torres-Hernandez; Mautin Hundeyin; Vishnu Raj Kumar Mani; Antonina Avanzi; Daniel Tippens; Rajkishen Narayanan; Jung Eun Jang; Elliot Newman; Venu Gopal Pillarisetty; Michael Loran Dustin; Dafna Bar-Sagi; Cristina Hajdu; George Miller

doi:10.1016/j.cell.2016.07.046

γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Donnele Daley
, Constantinos Pantelis Zambirinis
, Lena Seifert
, Neha Akkad
, Navyatha Mohan
, Gregor Werba
, Rocky Barilla
, Alejandro Torres-Hernandez
, Mautin Hundeyin
, Vishnu Raj Kumar Mani
, Antonina Avanzi
, Daniel Tippens
, Rajkishen Narayanan
, Jung Eun Jang
, Elliot Newman
, Venu Gopal Pillarisetty
, Michael Loran Dustin
, Dafna Bar-Sagi
, Cristina Hajdu
, George Miller

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

307 Scopus citations

Abstract

Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4⁺ and CD8⁺ T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

Original language	English
Pages (from-to)	1485-1499.e15
Journal	Cell
Volume	166
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2016.07.046
State	Published - Sep 8 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Funding

This work was supported by grants for the German Research Foundation (L.S.), the National Pancreas Foundation (C.P.Z.), the Pancreatic Cancer Action Network (G.M.), the Lustgarten Foundation (G.M.), and National Institute of Health Awards CA155649 (G.M.), CA168611 (G.M.), and CA193111 (G.M. and A.T.-H.). We thank the New York University Langone Medical Center (NYU LMC) Histopathology Core Facility, the NYU LMC Flow Cytometry Core Facility, the NYU LMC Microscopy Core Facility, and the NYU LMC BioRepository Center, each supported in part by the Cancer Center Support Grant P30CA016087 and by grant UL1 TR000038 from the National Center for the Advancement of Translational Science (NCATS).

Funders	Funder number
Markey Cancer Center's Cancer Center Support	P30CA016087, UL1 TR000038
National Center for the Advancement of Translational Science
National Institutes of Health (NIH)	CA168611, CA155649
National Childhood Cancer Registry – National Cancer Institute	T32CA193111
Pancreatic Cancer Action Network
National Pancreas Foundation
Lustgarten Foundation
NYU Langone Medical Center, Division of Cardiology
Deutsche Forschungsgemeinschaft

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Kras
cancer
checkpoint ligands

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1016/j.cell.2016.07.046

Cite this

Daley, D., Zambirinis, C. P., Seifert, L., Akkad, N., Mohan, N., Werba, G., Barilla, R., Torres-Hernandez, A., Hundeyin, M., Mani, V. R. K., Avanzi, A., Tippens, D., Narayanan, R., Jang, J. E., Newman, E., Pillarisetty, V. G., Dustin, M. L., Bar-Sagi, D., Hajdu, C., & Miller, G. (2016). γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation. Cell, 166(6), 1485-1499.e15. https://doi.org/10.1016/j.cell.2016.07.046

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title = "γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation",

abstract = "Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40\% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.",

keywords = "Kras, cancer, checkpoint ligands",

author = "Donnele Daley and Zambirinis, \{Constantinos Pantelis\} and Lena Seifert and Neha Akkad and Navyatha Mohan and Gregor Werba and Rocky Barilla and Alejandro Torres-Hernandez and Mautin Hundeyin and Mani, \{Vishnu Raj Kumar\} and Antonina Avanzi and Daniel Tippens and Rajkishen Narayanan and Jang, \{Jung Eun\} and Elliot Newman and Pillarisetty, \{Venu Gopal\} and Dustin, \{Michael Loran\} and Dafna Bar-Sagi and Cristina Hajdu and George Miller",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = sep,

day = "8",

doi = "10.1016/j.cell.2016.07.046",

language = "English",

volume = "166",

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Daley, D, Zambirinis, CP, Seifert, L, Akkad, N, Mohan, N, Werba, G, Barilla, R, Torres-Hernandez, A, Hundeyin, M, Mani, VRK, Avanzi, A, Tippens, D, Narayanan, R, Jang, JE, Newman, E, Pillarisetty, VG, Dustin, ML, Bar-Sagi, D, Hajdu, C & Miller, G 2016, 'γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation', Cell, vol. 166, no. 6, pp. 1485-1499.e15. https://doi.org/10.1016/j.cell.2016.07.046

TY - JOUR

T1 - γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

AU - Daley, Donnele

AU - Zambirinis, Constantinos Pantelis

AU - Seifert, Lena

AU - Akkad, Neha

AU - Mohan, Navyatha

AU - Werba, Gregor

AU - Barilla, Rocky

AU - Torres-Hernandez, Alejandro

AU - Hundeyin, Mautin

AU - Mani, Vishnu Raj Kumar

AU - Avanzi, Antonina

AU - Tippens, Daniel

AU - Narayanan, Rajkishen

AU - Jang, Jung Eun

AU - Newman, Elliot

AU - Pillarisetty, Venu Gopal

AU - Dustin, Michael Loran

AU - Bar-Sagi, Dafna

AU - Hajdu, Cristina

AU - Miller, George

PY - 2016/9/8

Y1 - 2016/9/8

N2 - Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

AB - Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted ∼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αβT cells. Although αβT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4+ and CD8+ T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.

KW - Kras

KW - cancer

KW - checkpoint ligands

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UR - https://www.scopus.com/pages/publications/84986296840#tab=citedBy

U2 - 10.1016/j.cell.2016.07.046

DO - 10.1016/j.cell.2016.07.046

M3 - Article

C2 - 27569912

AN - SCOPUS:84986296840

SN - 0092-8674

VL - 166

SP - 1485-1499.e15

JO - Cell

JF - Cell

IS - 6

ER -

γδ T Cells Support Pancreatic Oncogenesis by Restraining αβ T Cell Activation

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

ASJC Scopus subject areas

Access to Document

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