Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells

Elisa Matas-Rico, Elselien Frijlink, Irene van der Haar Àvila, Apostolos Menegakis, Maaike van Zon, Andrew J. Morris, Jan Koster, Fernando Salgado-Polo, Sander de Kivit, Telma Lança, Antonio Mazzocca, Zoë Johnson, John Haanen, Ton N. Schumacher, Anastassis Perrakis, Inge Verbrugge, Joost H. van den Berg, Jannie Borst, Wouter H. Moolenaar

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38 Citations (Scopus)

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.
Original languageEnglish
Article number110013
JournalCell reports
Volume37
Issue number7
DOIs
Publication statusPublished - 16 Nov 2021

Keywords

  • G protein-coupled receptors
  • T cells
  • anti-cancer vaccination
  • autotaxin
  • chemorepulsion
  • immunotherapy
  • lysophosphatidic acid
  • melanoma
  • single-cell RNAseq
  • tumor microenvironment

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