RT Journal Article
T1 Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8(+) T cells
A1 Matas-Rico, Elisa
A1 Frijlink, Elselien
A1 Avila, Irene van der Haar
A1 Menegakis, Apostolos
A1 van Zon, Maaike
A1 Morris, Andrew J.
A1 Koster, Jan
A1 Salgado-Polo, Fernando
A1 de Kivit, Sander
A1 Lanc, Telma
A1 Mazzocca, Antonio
A1 Johnson, Zoe
A1 Haanen, John
A1 Schumacher, Ton N.
A1 Perrakis, Anastassis
A1 Verbrugge, Inge
A1 van den Berg, Joost H.
A1 Borst, Jannie
A1 Moolenaar, Wouter H.
K1 Lysophosphatidic acid receptor
K1 Lysophospholipase-d
K1 Identification
K1 Exclusion
K1 Pathways
K1 Binding
K1 Microenvironment
K1 Fibroblasts
K1 Metastasis
K1 Chemokines
AB 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 G alpha(12/13)-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.
PB Cell press
SN 2211-1247
YR 2021
FD 2021-11-16
LK https://hdl.handle.net/10668/27827
UL https://hdl.handle.net/10668/27827
LA en
DS RISalud
RD Apr 12, 2025