PuSH - Publication Server of Helmholtz Zentrum München: Enforced sialyl-Lewis-X (sLeX) display in E-selectin ligands by exofucosylation is dispensable for CD19-CAR T-cell activity and bone marrow homing.

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Sánchez-Martínez, D.* ; Gutiérrez-Agüera, F.* ; Romecin, P.* ; Vinyoles, M.* ; Palomo, M.* ; Tirado, N.* ; Zanetti, S.R.* ; Juan, M.* ; Carlet, M. ; Jeremias, I. ; Menéndez, P.*

Enforced sialyl-Lewis-X (sLeX) display in E-selectin ligands by exofucosylation is dispensable for CD19-CAR T-cell activity and bone marrow homing.

Clin. Transl. Med. 11:e280 (2021)

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CD19-directed chimeric antigen receptors (CAR) T cells induce impressive rates of complete response in advanced B-cell malignancies, specially in B-cell acute lymphoblastic leukemia (B-ALL). However, CAR T-cell-treated patients eventually progress due to poor CAR T-cell persistence and/or disease relapse. The bone marrow (BM) is the primary location for acute leukemia. The rapid/efficient colonization of the BM by systemically infused CD19-CAR T cells might enhance CAR T-cell activity and persistence, thus, offering clinical benefits. Circulating cells traffic to BM upon binding of tetrasaccharide sialyl-Lewis X (sLeX)-decorated E-selectin ligands (sialofucosylated) to the E-selectin receptor expressed in the vascular endothelium. sLeX-installation in E-selectin ligands is achieved through an ex vivo fucosylation reaction. Here, we sought to characterize the basal and cell-autonomous display of sLeX in CAR T-cells activated using different cytokines, and to assess whether exofucosylation of E-selectin ligands improves CD19-CAR T-cell activity and BM homing. We report that cell-autonomous sialofucosylation (sLeX display) steadily increases in culture- and in vivo-expanded CAR T cells, and that, the cytokines used during T-cell activation influence both the degree of such endogenous sialofucosylation and the CD19-CAR T-cell efficacy and persistence in vivo. However, glycoengineered enforced sialofucosylation of E-selectin ligands was dispensable for CD19-CAR T-cell activity and BM homing in multiple xenograft models regardless the cytokines employed for T-cell expansion, thus, representing a dispensable strategy for CD19-CAR T-cell therapy.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Bm Homing ; Car T-cells ; E-selectin Ligands ; Exofucosylation

ISSN (print) / ISBN 2001-1326

e-ISSN 2001-1326

Journal Clinical and translational medicine

Quellenangaben Volume: 11, Issue: 2, Article Number: e280

Publisher Springer

Publishing Place The Atrium, Southern Gate, Chichester Po19 8sq, W Sussex, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)

Grants Spanish Association against cancer (AECC, Semilla 2019)
"la Caixa" Foundation
Fundacion Uno entre Cienmil
Spanish Ministry of Economy and Competitiveness
European Research Council