RT Conference Proceedings
T1 Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
A1 Matas-Rico, Elisa
A1 Frijlink, Elselien
A1 Morris, Andrew
A1 Moolenaar, Wouter H
A1 Koster, Jan
A1 van der Haar, Irene
A1 Menegakis, Apostolos
A1 van Zon, Maaike
A1 Salgado-Polo, Fernando
A1 De Kivit, Sander
A1 Johnson, Zoe
A1 Haanen, John
A1 Schumacher, Ton
A1 Borst, Jannie
A1 Verbrugge, Inge
A1 van den Berg, Joost
A1 Perrakis, Anastassis
AB To improve the efficacy of immunotherapy, it is essential to better understand how cytotoxic CD8+ T cells infiltrate into tumors. Here, we examine a role for autotaxin (ATX) in this process. ATX (encoded by ENPP2) is a secreted phospholipase that produces the lipid mediator lysophosphatidic acid (LPA) to regulate multiple biological functions via specific G protein-coupled receptors, termed LPAR1-6. ATX/LPA promotes tumor cell migration via LPAR1 and T-cell motility via LPAR2, yet its actions in the tumor microenvironment remain unclear. Here, we show that tumor-intrinsic ATX suppresses T-cell infiltration to impede anti-tumor immunity, and identify LPAR6 as a T-cell migration inhibitory receptor. Hence, ATX inhibition may show clinical benefit for patients with cancer.  We find that ATX secreted by melanoma cells is a chemo-repellent for ex vivo expanded tumor-infiltrating lymphocytes (TILs) and peripheral CD8+ T cells, overruling chemokine activity. Mechanistically, T-cell repulsion is mediated by G12/13-coupled LPAR6, which is highly expressed in immune cells. Contrary to prevailing notions, secreted ATX is bioactive at physiologically insignificant steady-state LPA levels, revealing its secondary function as an LPA carrier or chaperone. Upon anti-cancer vaccination of tumor-bearing mice, tumor-intrinsic 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 immune control. Moreover, ENPP2 expression in melanoma tumors – in both malignant and stromal cells – is associated with reduced T-cell infiltration, as inferred from single-cell transcriptomics. These findings highlight an unexpected role for the pro-metastatic ATX-LPAR axis in suppressing CD8+ T cell infiltration and anti-tumor immunity.
YR 2022
FD 2022
LK https://hdl.handle.net/10630/24539
UL https://hdl.handle.net/10630/24539
LA eng
DS RIUMA. Repositorio Institucional de la Universidad de Málaga
RD 19 ene 2026