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.2022-07-072022-07-072021-11-16Matas-Rico E, Frijlink E, van der Haar Àvila I, Menegakis A, van Zon M, Morris AJ, et al. Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells. Cell Rep. 2021 Nov 16;37(7):110013http://hdl.handle.net/10668/3753Autotaxin (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.enAttribution-NonCommercial-NoDerivatives 4.0 InternacionalAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/G protein-coupled receptorsT cellsAnti-cancer vaccinationAutotaxinChemorepulsionImmunotherapyIysophosphatidic acidMelanomaSingle-cell RNAseqTumor microenvironmentReceptores acoplados a proteínas GLinfocitos TInmunoterapiaMicroambiente tumoralNeoplasiasCélulasMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::CD8-Positive T-LymphocytesMedical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, TumorMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Movement::ChemotaxisMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunization::Immunotherapy, Active::VaccinationMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::Lymphocytes, Tumor-InfiltratingMedical Subject Headings::Chemicals and Drugs::Lipids::Membrane Lipids::Phospholipids::Glycerophosphates::Phosphatidic Acids::LysophospholipidsMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BLMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Diester HydrolasesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic AcidMedical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironmentresearch article34788605Acceso abierto10.1016/j.celrep.2021.1100132211-1247PMC8761359