%0 Journal Article
%A Matas-Rico, Elisa
%A Frijlink, Elselien
%A van der Haar Àvila, Irene
%A Menegakis, Apostolos
%A van Zon, Maaike
%A Morris, Andrew J.
%A Koster, Jan
%A Salgado-Polo, Fernando
%A de Kivit, Sander
%A Lança, Telma
%A Mazzocca, Antonio
%A Johnson, Zoë
%A Haanen, John
%A Schumacher, Ton N.
%A Perrakis, Anastassis
%A Verbrugge, Inge
%A van den Berg, Joost H.
%A Borst, Jannie
%A Moolenaar, Wouter H.
%T Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
%D 2021
%U http://hdl.handle.net/10668/3753
%X 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.
%K G protein-coupled receptors
%K T cells
%K Anti-cancer vaccination
%K Autotaxin
%K Chemorepulsion
%K Immunotherapy
%K Iysophosphatidic acid
%K Melanoma
%K Single-cell RNAseq
%K Tumor microenvironment
%K Receptores acoplados a proteínas G
%K Linfocitos T
%K Inmunoterapia
%K Microambiente tumoral
%K Neoplasias
%K Células
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