Enforced E-selectin ligand installation enhances homing and efficacy of adoptively transferred T cells

Abstract

Adoptive T-cell transfer has revolutionized the treatment of hematological malignancies. However, this approach has had very limited success in treating solid tumors, largely due to inadequate infiltration of vascularly administered T cells at tumor sites. The shear-resistant interaction between endothelial E-selectin and its cognate ligand expressed on leukocytes, sialyl Lewis X (sLeX), is an essential prerequisite for extravasation of circulating leukocytes. Here, we report that enforced E-selectin ligand expression (enforced sLeX display) on antigen-specific T cells can be achieved by fucosylating cells via cell surface treatment with the human 1-3-fucosyltransferase, FUT6 ("exofucosylation"), or via Golgi-targeted FUT6 overexpression ("Golgi-fucosylation"). However, despite comparable E-selectin binding, only sLeX-modified T cells engendered by exofucosylation, not by Golgi-fucosylation, exhibited enhanced parenchymal infiltration of target malignant sites. This heightened homing yielded significantly improved therapeutic efficacy in various murine syngeneic and xenograft cancer models, including subcutaneous solid tumors, lymphoma and leukemia, as well as lung and bone marrow metastases. Therefore, exofucosylation represents a promising strategy to improve the efficacy of adoptive T-cell therapy, particularly in the treatment of solid tumors and metastatic disease.