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oai:repisalud.isciii.es:20.500.12105/185032024-11-28T14:47:27Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927
Repisalud author Matas-Rico, Elisa author Frijlink, Elselien author van der Haar Àvila, Irene author Menegakis, Apostolos author van Zon, Maaike author Morris, Andrew J. author Koster, Jan author Salgado-Polo, Fernando author de Kivit, Sander author Lança, Telma author Mazzocca, Antonio author Johnson, Zoë author Haanen, John author Schumacher, Ton N. author Perrakis, Anastassis author Verbrugge, Inge author van den Berg, Joost H. author Borst, Jannie author Moolenaar, Wouter H. 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. 2024-02-19T15:32:01Z 2024-02-19T15:32:01Z 2021-11-16 10.1016/j.celrep.2021.110013 2211-1247 Cell Reports http://hdl.handle.net/10668/3753 34788605 http://hdl.handle.net/20.500.12105/18503 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. eng 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 Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells research article