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Title: Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
Authors: Matas-Rico, Elisa
Frijlink, Elselien
van der Haar Àvila, Irene
Menegakis, Apostolos
van Zon, Maaike
Morris, Andrew J.
Koster, Jan
Salgado-Polo, Fernando
de Kivit, Sander
Lança, Telma
Mazzocca, Antonio
Johnson, Zoë
Haanen, John
Schumacher, Ton N.
Perrakis, Anastassis
Verbrugge, Inge
van den Berg, Joost H.
Borst, Jannie
Moolenaar, Wouter H.
metadata.dc.contributor.authoraffiliation: [Matas-Rico,E; Salgado-Polo,F; Perrakis,A; Moolenaar,WH] Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands. [Frijlink,E; van der Haar Àvila,I; de Kivit,S; Verbrugge,I; Borst,J] Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [Frijlink,E; van der Haar Àvila,I; Menegakis,A; Salgado-Polo,F; de Kivit,S; Lança,T; Schumacher,TN; Perrakis,A; Verbrugge,I; Borst,J] Oncode Institute, Utrecht, the Netherlands. [Menegakis,A] Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [van Zon,M; Lança,T; Haanen,J; Schumacher,TN; van den Berg,JH] Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. [Morris,AJ] Division of Cardiovascular Medicine, Gill Heart Institute and Lexington Veterans Affairs Medical Center, University of Kentucky, Lexington, KY, USA. [Koster,J] Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, Amsterdam, the Netherlands. [Mazzocca,A] Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy. [Johnson,Z] Onctura SA, Campus Biotech Innovation Park, Geneva, Switzerland. [Matas-Rico,E] Department of Cell Biology, Genetics and Physiology, Malaga University, Malaga, Spain. [Matas-Rico,E] Genitourinary Cancer Translational Research Group, The Institute of Biomedical Research in Malaga (IBIMA), Malaga, Spain. [van der Haar Àvila,I] Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Amsterdam, the Netherlands. [de Kivit,S; Borst,J] Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. [Verbrugge,I] Janssen Pharmaceutica NV, Beerse, Belgium. [van den Berg,JH] CellPoint BV, Oegstgeest, the Netherlands.
Keywords: G protein-coupled receptors;T cells;Anti-cancer vaccination;Autotaxin;Chemorepulsion;Immunotherapy;Iysophosphatidic acid;Melanoma;Single-cell RNAseq;Tumor microenvironment;Receptores acoplados a proteínas G;Linfocitos T;Inmunoterapia;Microambiente tumoral;Neoplasias;Células
metadata.dc.subject.mesh: Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::CD8-Positive T-Lymphocytes
Medical Subject Headings::Anatomy::Cells::Cells, Cultured::Cell Line::Cell Line, Tumor
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Movement::Chemotaxis
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Immunomodulation::Immunotherapy::Immunization::Immunotherapy, Active::Vaccination
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::Lymphocytes, Tumor-Infiltrating
Medical Subject Headings::Chemicals and Drugs::Lipids::Membrane Lipids::Phospholipids::Glycerophosphates::Phosphatidic Acids::Lysophospholipids
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice::Mice, Inbred Strains::Mice, Inbred C57BL
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Esterases::Phosphoric Diester Hydrolases
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, G-Protein-Coupled::Receptors, Lysophospholipid::Receptors, Lysophosphatidic Acid
Medical Subject Headings::Phenomena and Processes::Cell Physiological Phenomena::Cellular Microenvironment::Tumor Microenvironment
Issue Date: 16-Nov-2021
Publisher: Cell Press
Citation: Matas-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):110013
Abstract: Autotaxin (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.
metadata.dc.identifier.doi: 10.1016/j.celrep.2021.110013
ISSN: 2211-1247 (Online)
Appears in Collections:01- Artículos - IBIMA. Instituto de Investigación Biomédica de Málaga

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