TY - JOUR
T1 - Invariant natural killer T-cell subsets have diverse graft-versus-host-disease–preventing and antitumor effects
AU - Maas-Bauer, Kristina
AU - Lohmeyer, Juliane K.
AU - Hirai, Toshihito
AU - Ramos, Teresa Lopes
AU - Fazal, Furqan M.
AU - Litzenburger, Ulrike M.
AU - Yost, Kathryn E.
AU - Ribado, Jessica V.
AU - Kambham, Neeraja
AU - Wenokur, Arielle S.
AU - Lin, Po Yu
AU - Alvarez, Maite
AU - Mavers, Melissa
AU - Baker, Jeanette
AU - Bhatt, Ami S.
AU - Chang, Howard Y.
AU - Simonetta, Federico
AU - Negrin, Robert S.
N1 - Funding Information:
The authors thank Dhananjay Wagh, Xuhuai Ji, and John Coller at the Stanford Functional Genomics Facility for their excellent technical assistance in the genomics analysis. In addition, the authors acknowledge Mitchell Kronenberg for the kind gift of the A20-CD1d cell line. This work was supported by grants from the National Institutes of Health (NIH) (National Heart, Lung, and Blood Institute, P01 HL075462, and the National Cancer Institute, R01 CA23158201, R.S.N.; National Human Genome Research Institute, RM1-HG007735, H.Y.C.), the German Cancer Aid (Mildred Scheel Postdoctoral Fellowship, K.M.-B. and J.K.L.), the Geneva University Hospitals Fellowship (F.S.), the Swiss Cancer League (BIL KLS 3806-02-2016, F.S.), the Fondation de Bienfaisance Valeria Rossi di Montelera (Eugenio Litta Fellowship, F.S.), the American Society for Blood and Marrow Transplantation (New Investigator Award 2018, F.S.), the Dubois-Ferrière-Dinu-Lipatti Foundation, F.S. the National Science Foundation (Graduate Research Fellowship DGE‐114747, J.V.R.), the American Association for Cancer Research (Millennium Fellowship in Lymphoma Research 15-40-38-ALVA, M.A.), the St. Baldrick's Fellowship with generous support from the Rays of Hope Hero Fund (M.M.), and the Parker Institute for Cancer Immunotherapy (H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. Flow cytometry analysis for this project was conducted on instruments in the Stanford Shared FACS Facility purchased by using an NIH S10 Shared Instrumentation Grant (S10RR027431-01). Sequencing was performed on instruments in the Stanford Functional Genomics Facility, including the Illumina HiSeq 4000 purchased by using an NIH S10 Shared Instrumentation Grant (S10OD018220).
Funding Information:
This work was supported by grants from the National Institutes of Health (NIH) (National Heart, Lung, and Blood Institute, P01 HL075462, and the National Cancer Institute, R01 CA23158201, R.S.N.; National Human Genome Research Institute, RM1-HG007735, H.Y.C.), the German Cancer Aid (Mildred Scheel Postdoctoral Fellowship, K.M.-B. and J.K.L.), the Geneva University Hospitals Fellowship (F.S.), the Swiss Cancer League (BIL KLS 3806-02-2016, F.S.), the Fondation de Bienfaisance Valeria Rossi di Montelera (Eugenio Litta Fellowship, F.S.), the American Society for Blood and Marrow Transplantation (New Investigator Award 2018, F.S.), the Dubois-Ferrière-Dinu-Lipatti Foundation, F.S., the National Science Foundation (Graduate Research Fellowship DGE‐114747, J.V.R.), the American Association for Cancer Research (Millennium Fellowship in Lymphoma Research 15-40-38-ALVA, M.A.), the St. Baldrick's Fellowship with generous support from the Rays of Hope Hero Fund (M.M.), and the Parker Institute for Cancer Immunotherapy (H.Y.C.). H.Y.C. is an Investigator of the Howard Hughes Medical Institute. Flow cytometry analysis for this project was conducted on instruments in the Stanford Shared FACS Facility purchased by using an NIH S10 Shared Instrumentation Grant (S10RR027431-01). Sequencing was performed on instruments in the Stanford Functional Genomics Facility, including the Illumina HiSeq 4000 purchased by using an NIH S10 Shared Instrumentation Grant (S10OD018220).
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/9/9
Y1 - 2021/9/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114449446&partnerID=8YFLogxK
U2 - 10.1182/blood.2021010887
DO - 10.1182/blood.2021010887
M3 - Article
C2 - 34036317
AN - SCOPUS:85114449446
SN - 0006-4971
VL - 138
SP - 858
EP - 870
JO - Blood
JF - Blood
IS - 10
ER -