Format

Send to

Choose Destination
J Biol Chem. 2019 Nov 29;294(48):18465-18474. doi: 10.1074/jbc.RA119.011134. Epub 2019 Oct 18.

Glycoengineering of chimeric antigen receptor (CAR) T-cells to enforce E-selectin binding.

Author information

1
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115.
2
Program of Excellence in Glycosciences, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
3
Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02129.
4
Department of Dermatology and Harvard Skin Disease Research Center, Brigham and Women's Hospital, Boston, Massachusetts 02115 sackstein@fiu.edu.
5
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
6
Department of Translational Medicine, Herbert Wertheim College of Medicine, and Translational Glycobiology Institute, Florida International University, Miami, Florida 33199.

Abstract

Tissue colonization (homing) by blood-borne cells critically hinges on the ability of the cells to adhere to vascular endothelium with sufficient strength to overcome prevailing hemodynamic shear stress. These adhesive interactions are most effectively engendered via binding of the endothelial lectin E-selectin (CD62E) to its cognate ligand, sialyl Lewis-X (sLe X ), displayed on circulating cells. Although chimeric antigen receptor (CAR) T-cell immunotherapy holds promise for treatment of various hematologic and non-hematologic malignancies, there is essentially no information regarding the efficiency of CAR T-cell homing. Accordingly, we performed integrated biochemical studies and adhesion assays to examine the capacity of human CAR T-cells to engage E-selectin. Our data indicate that CAR T-cells do not express sLe X and do not bind E-selectin. However, enforced sLe X display can be achieved on human CAR T-cells by surface fucosylation, with resultant robust E-selectin binding under hemodynamic shear. Importantly, following intravascular administration into mice, fucosylated human CAR-T cells infiltrate marrow with 10-fold higher efficiency than do unfucosylated cells. Collectively, these findings indicate that custom installation of sLe X programs tissue colonization of vascularly administered human CAR T-cells, offering a readily translatable strategy to augment tissue delivery, thereby lowering the pertinent cell dosing and attendant cell production burden, for CAR T-cell immunotherapy applications.

KEYWORDS:

CAR T cell; E-selectin ligand; cancer therapy; fucosyltransferase; glycobiology; glycosylation; immunotherapy; sLeX; sialyl Lewis X; translational glycobiology

PMID:
31628196
PMCID:
PMC6885642
[Available on 2020-11-29]
DOI:
10.1074/jbc.RA119.011134

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center