Matas-Rico, ElisaFrijlink, Elselienvan der Haar Àvila, IreneMenegakis, Apostolosvan Zon, MaaikeMorris, Andrew J.Koster, JanSalgado-Polo, Fernandode Kivit, SanderLança, TelmaMazzocca, AntonioJohnson, ZoëHaanen, JohnSchumacher, Ton N.Perrakis, AnastassisVerbrugge, Ingevan den Berg, Joost H.Borst, JannieMoolenaar, Wouter H.2024-02-192024-02-192021-11-16http://hdl.handle.net/10668/3753http://hdl.handle.net/20.500.12105/18503Autotaxin (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 Gα12/13-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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/G protein-coupled receptorsT cellsAnti-cancer vaccinationAutotaxinChemorepulsionImmunotherapyIysophosphatidic acidMelanomaSingle-cell RNAseqTumor microenvironmentReceptores acoplados a proteínas GLinfocitos TInmunoterapiaMicroambiente tumoralNeoplasiasCélulasAnimalsCD8-Positive T-LymphocytesCell Line, TumorChemotaxisVaccinationHumansLymphocytes, Tumor-InfiltratingLysophospholipidsMiceMice, Inbred C57BLPhosphoric Diester HydrolasesReceptors, Lysophosphatidic AcidTumor MicroenvironmentAttribution-NonCommercial-NoDerivatives 4.0 International3478860510.1016/j.celrep.2021.1100132211-1247Cell Reportsopen access