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

Abstract

Both 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.

Từ khóa


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Journal of extracellular vesicles

Tập 10 Số 4

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