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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\n                    <jats:italic>in vitro<\/jats:italic>\n                    decreased VCAM1, CX3CL1, and CXCL10 expression in HUVECs, mirroring the same decrease found in Treg cocultures. In the APC\n                    <jats:sup>min\/+<\/jats:sup>\n                    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\u2010cell migration into tumors.\n                  <\/jats:p>","DOI":"10.1002\/eji.202149208","type":"journal-article","created":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T06:21:08Z","timestamp":1626502868000},"page":"2317-2329","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Regulatory T cells reduce endothelial neutral sphingomyelinase 2 to prevent T\u2010cell migration into tumors"],"prefix":"10.1002","volume":"51","author":[{"given":"Paulina","family":"Akeus","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology Institute of Biomedicine The Sahlgrenska Academy at University of Gothenburg  Gothenburg 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