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00925njm 22002777a 4500 dc Matas-Rico, Elisa author Moolenaar, Wouter H 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 2021 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. Matas-Rico, Elisa et al. Cell Reports, Volume 37, Issue 7, 110013 https://hdl.handle.net/10630/32707 https://doi.org/10.1016/j.celrep.2021.110013 Tumores Inmunoterapia Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells