Matas-Rico, ElisaFrijlink, ElselienAvila, Irene van der HaarMenegakis, Apostolosvan Zon, MaaikeMorris, Andrew J.Koster, JanSalgado-Polo, Fernandode Kivit, SanderLanc, TelmaMazzocca, AntonioJohnson, ZoeHaanen, JohnSchumacher, Ton N.Perrakis, AnastassisVerbrugge, Ingevan den Berg, Joost H.Borst, JannieMoolenaar, Wouter H.2025-01-072025-01-072021-11-162211-1247https://hdl.handle.net/10668/27827Autotaxin (ATX; ENPP2) produces lysophosphatidic acid (LPA) that regulates multiple biological functions via cognate G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis via LPAR1 and T cell motility via LPAR2, yet its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes (TILs) and circulating CD8(+) T cells ex vivo, with ATX functioning as an LPA-producing chaperone. Mechanistically, T cell repulsion predominantly involves G alpha(12/13)-coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T cell responses but, importantly, suppresses tumor infiltration of cytotoxic CD8(+) T cells and thereby impairs tumor regression. Moreover, single-cell data from melanoma tumors are consistent with intratumoral ATX acting as a T cell repellent. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8(+) T cell infiltration to impede anti-tumor immunity, suggesting new therapeutic opportunities.enAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Lysophosphatidic acid receptorLysophospholipase-dIdentificationExclusionPathwaysBindingMicroenvironmentFibroblastsMetastasisChemokinesresearch article34788605open access10.1016/j.celrep.2021.110013http://www.cell.com/article/S2211124721014959/pdf720347900005