Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T-cell migration into tumors.

Abstract

Endothelial cells are key regulators of transendothelial migration and their secretion of chemokines and expression of adhesion molecules facilitates lymphocyte entry into tissues. Previously, we demonstrated that Tregs can reduce transendothelial migration of T cells into tumors by decreasing endothelial CXCL10 secretion, but the mechanism by which this occurs is still not known. In this study, we aimed to define how Tregs decrease transendothelial migration into tumors. mRNA sequencing of intestinal tumor endothelial cells from Treg depleted mice identified neutral sphingomyelinase 2 (nSMase2) as a gene downregulated in the presence of Tregs. nSMase2 is expressed in human umbilical vein endothelial cells (HUVECs) and was decreased after coculture with Tregs. Furthermore, blocking of nSMase2 activity in vitro decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APCmin/+ mouse model of intestinal cancer, nSMase2 is lower in tumor endothelial cells than in unaffected small intestine and chronic treatment with a nSMase2 inhibitor suppressed the increased migration that is otherwise seen in the absence of Tregs. We conclude that nSMase2 is an important mediator in endothelial cells supporting transendothelial migration, which may be targeted by Tregs to reduce T-cell migration into tumors.

• Authors: Paulina Akeus, Louis Szeponik, Veronica Langenes, Viktoria Karlsson, Patrik Sundström, Elinor Bexe-Lindskog, Carolyn Tallon, Barbara S Slusher, Marianne Quiding-Järbrink
• Journal: European journal of immunology (Eur J Immunol) Vol. 51 Issue 9 Pg. 2317-2329 (09 2021) ISSN: 1521-4141 [Electronic] Germany
• PMID: 34272885 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.

Chemical References

• CX3CL1 protein, human
• CXCL10 protein, human
• Cell Adhesion Molecules
• Chemokine CX3CL1
• Chemokine CXCL10
• VCAN protein, human
• Versicans
• Smpd3 protein, mouse
• Sphingomyelin Phosphodiesterase

Topics

• Animals
• Cell Adhesion Molecules (biosynthesis)
• Cell Line
• Chemokine CX3CL1 (biosynthesis)
• Chemokine CXCL10 (biosynthesis, metabolism)
• Colonic Neoplasms (immunology, pathology)
• Down-Regulation
• Female
• Human Umbilical Vein Endothelial Cells
• Humans
• Lymphocytes, Tumor-Infiltrating (immunology)
• Male
• Mice
• Mice, Transgenic
• Sphingomyelin Phosphodiesterase (metabolism)
• T-Lymphocyte Subsets (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Transendothelial and Transepithelial Migration (physiology)
• Versicans (biosynthesis)