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 journalArticlepeer-review

262 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 languageEnglish
Pages (from-to)1485-1499.e15
JournalCell
Volume166
Issue number6
DOIs
StatePublished - Sep 8 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

  • Kras
  • cancer
  • checkpoint ligands

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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