Invariant natural killer T-cell subsets have diverse graft-versus-host-disease-preventing and antitumor effects

Authors

Kristina Maas-Bauer
Juliane K Lohmeyer
Toshihito Hirai
Teresa Lopes Ramos
Furqan M Fazal
Ulrike M Litzenburger
Kathryn E Yost
Jessica V Ribado
Neeraja Kambham
Arielle S Wenokur
Po-Yu Lin
Maite Alvarez
Melissa Mavers
Jeanette Baker
Ami S Bhatt
Howard Y Chang
Federico Simonetta
Robert S Negrin

Publication Date

9-9-2021

Journal

Blood

DOI

10.1182/blood.2021010887

PMID

34036317

PMCID

PMC8432044

PubMedCentral® Posted Date

5-25-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Epigenomics, Female, Gene Expression Profiling, Graft vs Host Disease, Graft vs Tumor Effect, Lymphocyte Activation, Lymphoma, B-Cell, Male, Mice, Natural Killer T-Cells, Neoplasms, Experimental

Abstract

Invariant natural killer T (iNKT) cells are a T-cell subset with potent immunomodulatory properties. Experimental evidence in mice and observational studies in humans indicate that iNKT cells have antitumor potential as well as the ability to suppress acute and chronic graft-versus-host-disease (GVHD). Murine iNKT cells differentiate during thymic development into iNKT1, iNKT2, and iNKT17 sublineages, which differ transcriptomically and epigenomically and have subset-specific developmental requirements. Whether distinct iNKT sublineages also differ in their antitumor effect and their ability to suppress GVHD is currently unknown. In this work, we generated highly purified murine iNKT sublineages, characterized their transcriptomic and epigenomic landscape, and assessed specific functions. We show that iNKT2 and iNKT17, but not iNKT1, cells efficiently suppress T-cell activation in vitro and mitigate murine acute GVHD in vivo. Conversely, we show that iNKT1 cells display the highest antitumor activity against murine B-cell lymphoma cells both in vitro and in vivo. Thus, we report for the first time that iNKT sublineages have distinct and different functions, with iNKT1 cells having the highest antitumor activity and iNKT2 and iNKT17 cells having immune-regulatory properties. These results have important implications for the translation of iNKT cell therapies to the clinic for cancer immunotherapy as well as for the prevention and treatment of GVHD.

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