4.7 Article

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

Journal

BLOOD
Volume 138, Issue 10, Pages 858-870

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021010887

Keywords

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Funding

  1. National Institutes of Health (NIH) (National Heart, Lung, and Blood Institute) [P01 HL075462]
  2. National Cancer Institute [R01 CA23158201]
  3. National Human Genome Research Institute [RM1-HG007735]
  4. German Cancer Aid (Mildred Scheel Postdoctoral Fellowship)
  5. Geneva University Hospitals Fellowship
  6. Swiss Cancer League [3806-02-2016]
  7. Fondation de Bienfaisance Valeria Rossi di Montelera (Eugenio Litta Fellowship)
  8. American Society for Blood and Marrow Transplantation
  9. Dubois-Ferriere-Dinu-Lipatti Foundation
  10. National Science Foundation [DGE-114747]
  11. American Association for Cancer Research [15-40-38-ALVA]
  12. St. Baldrick's Fellowship
  13. Rays of Hope Hero Fund
  14. Parker Institute for Cancer Immunotherapy
  15. Howard Hughes Medical Institute
  16. NIH [S10OD018220]
  17. [S10RR027431-01]

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Different sublineages of iNKT cells exhibit distinct functions, with iNKT1 cells showing the highest antitumor activity against murine B-cell lymphoma cells, while iNKT2 and iNKT17 cells have immune-regulatory properties. These findings have important implications for the development of iNKT cell therapies in cancer immunotherapy and GVHD prevention and treatment.
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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