WJMSC‐derived small extracellular vesicle enhance T cell suppression through PD‐L1

Journal of extracellular vesicles - Tập 10 Số 4 - 2021
Meizhang Li1, Rupal P. Soder2, Sunil Abhyankar3,2,4, Haitham Abdelhakim3, Mitchell W. Braun1, Camille V. Trinidad5, Harsh B. Pathak1,4, Ziyan Y. Pessetto1, Clayton Deighan6, Siddhartha Ganguly3, Buddhadeb Dawn7,2, Joseph P. McGuirk3,4, Neil Dunavin3,8, Andrew K. Godwin5,1,4
1Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas USA
2Midwest Stem Cell Therapy Center, University of Kansas Medical Center, Kansas City, Kansas, USA
3Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
4The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kansas, USA
5Department of Microbiology, Molecular Genetics and Immunology, Kansas City, Kansas, USA
6Nanoview Biosciences, Boston, Massachusetts, USA
7Department of Medicine, University of Nevada, Las Vegas, Nevada, USA
8Division of Hematology and Blood and Marrow Transplant, University of California San Francisco, San Francisco, California, USA

Tóm tắt

AbstractBoth mesenchymal stem cells (MSCs) and their corresponding small extracellular vesicles (sEVs, commonly referred to as exosomes) share similar immunomodulatory properties that are potentially beneficial for the treatment of acute graft versus host disease (aGvHD). We report that clinical grade Wharton's Jelly‐derived MSCs (WJMSCs) secrete sEVs enriched in programmed death‐ligand 1 (PD‐L1), an essential ligand for an inhibitory immune checkpoint. A rapid increase in circulating sEV‐associated PD‐L1 was observed in patients with aGvHD and was directly associated with the infusion time of clinical grade WJMSCs. In addition, in vitro inhibitory antibody mediated blocking of sEV‐associated PD‐L1 restored T cell activation (TCA), suggesting a functional inhibitory role of sEVs‐PD‐L1. PD‐L1‐deficient sEVs isolated from WJMSCs following CRISPR‐Cas9 gene editing fail to inhibit TCA. Furthermore, we found that PD‐L1 is essential for WJMSC‐derived sEVs to modulate T cell receptors (TCRs). Our study reveals an important mechanism by which therapeutic WJMSCs modulate TCR‐mediated TCA through sEVs or sEV‐carried immune checkpoints. In addition, our clinical data suggest that sEV‐associated PD‐L1 may be not only useful in predicting the outcomes from WJMSC clinical administration, but also in developing cell‐independent therapy for aGvHD patients.

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Tài liệu tham khảo

10.1038/nbt.2816

10.1161/01.CIR.0000084828.50310.6A

10.1016/j.pharmthera.2017.02.020

10.1038/nri3212

10.1056/NEJMra1514296

10.1002/ijc.32925

10.1002/term.2914

10.1016/j.immuni.2007.05.016

10.1016/j.molimm.2008.05.014

10.1016/j.cytogfr.2019.05.006

Cassady K., 2018, Regulation of GVHD and GVL activity via PD‐L1 interaction with PD‐1 and CD80, Frontiers in immunology, 9, 3061, 10.3389/fimmu.2018.03061

10.1182/blood-2006-12-022038

10.1038/nm1293

10.1038/nprot.2006.1

10.1038/s41586-018-0392-8

10.1007/s12026-016-8798-6

10.1126/science.1231143

10.1038/s41577-019-0264-y

10.1002/stem.2509

10.1038/bmt.2017.35

10.1002/acg2.32

10.3389/fimmu.2012.00297

10.3389/fimmu.2018.01943

10.1084/jem.20090847

10.1084/jem.192.7.1027

10.1002/stem.2759

10.4049/jimmunol.1400954

Fumihiko Tsushima S. Y., 2007, Interaction between B7‐H1 and PD‐1 determines initiation and reversal of T‐cell anergy, Blood, 110, 6

10.1016/j.stem.2018.05.004

10.1038/s41577-018-0020-8

10.3389/fimmu.2019.02663

10.1182/blood-2012-10-385591

10.1016/j.jcyt.2018.02.003

10.3390/cells9051157

10.1016/S1083-8791(99)70012-1

10.1016/j.bbmt.2019.08.029

10.4049/jimmunol.179.8.5064

10.1097/01.tp.0000256293.90270.e8

10.1038/leu.2014.41

10.1038/leu.2011.108

10.1016/j.bbmt.2020.01.018

10.1186/s13045-018-0680-7

10.1182/blood-2012-01-403063

Lugt V., 2013, ST2 as a marker for risk of therapy‐resistant graft‐versus‐host disease and death, New England Journal of Medicine, 368, 11

10.1016/j.bbmt.2014.12.025

10.1007/s12185-015-1915-9

10.1172/JCI91138

10.1038/s41536-019-0083-6

10.1016/j.cell.2019.02.016

10.1182/blood-2014-06-584789

10.1038/sj.bmt.1703111

10.1126/sciadv.aar2766

Rowan C. M., 2020, Assessment of ST2 for risk of death following graft‐versus‐host disease in the pediatric and adult age groups, Blood, 135, 1428, 10.1182/blood.2019002334

10.1172/JCI85796

10.1126/science.1247005

10.1038/s41581-018-0023-5

10.1007/s12015-020-10015-8

10.1038/leu.2015.89

10.1038/nrm.2017.125

Wolfgang Koestner M. H., 2011, PD‐L1 blockade effectively restores strong graft‐versus‐leukemia effects without graft‐versus‐host disease after delayed adoptive transfer of T‐cell receptor gene‐engineered allogeneic CD8+ T cells, Blood, 117, 12

10.1056/NEJMra1609337

10.1016/j.cellimm.2020.104113

10.1016/j.jcyt.2018.02.372

10.1002/jcp.26436

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Journal of extracellular vesicles

Tập 10 Số 4

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