Innate αβ T cells mediate antitumor immunity by orchestrating immunogenic macrophage programming

Mautin Hundeyin, Emma Kurz, Ankita Mishra, Juan Andres Kochen Rossi, Shannon M. Liudahl, Kenna R. Leis, Harshita Mehrotra, Mirhee Kim, Luisana E. Torres, Adesola Ogunsakin, Jason Link, Rosalie C. Sears, Shamilene Sivagnanam, Jeremy Goecks, K. M.Sadeq Islam, Igor Dolgalev, Shivraj Savadkar, Wei Wang, Berk Aykut, Joshua LeinwandBrian Diskin, Salma Adam, Muhammad Israr, Maeliss Gelas, Justin Lish, Kathryn Chin, Mohammad Saad Farooq, Benjamin Wadowski, Jingjing Wu, Suhagi Shah, Dennis O. Adeegbe, Smruti Pushalkar, Varshini Vasudevaraja, Deepak Saxena, Kwok Kin Wong, Lisa M. Coussens, George Miller

Research output: Contribution to journalArticlepeer-review

Abstract

Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4-CD8-NK1.1- innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets. SIGNIFICANCE: We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.

Original languageEnglish (US)
Pages (from-to)1288-1305
Number of pages18
JournalCancer Discovery
Volume9
Issue number9
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Innate αβ T cells mediate antitumor immunity by orchestrating immunogenic macrophage programming'. Together they form a unique fingerprint.

Cite this