2026-05-28T00:28:46Zhttps://riuma.uma.es/rest/oai/request

oai:riuma.uma.es:10630/245392026-02-03T12:22:20Zcom_10630_2254col_10630_37959

Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells Matas-Rico, Elisa Frijlink, Elselien Morris, Andrew Moolenaar, Wouter H Koster, Jan van der Haar, Irene Menegakis, Apostolos van Zon, Maaike Salgado-Polo, Fernando De Kivit, Sander Johnson, Zoe Haanen, John Schumacher, Ton Borst, Jannie Verbrugge, Inge van den Berg, Joost Perrakis, Anastassis 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. 2022-07-04T10:46:11Z 2022-07-04T10:46:11Z 2022 2022 conference output https://hdl.handle.net/10630/24539 eng EACR. 28TH CONGRESS OF THE EUROPEAN ASSOCIATION FOR CANCER RESEARCH. Innovative Cancer Science: Translating Biology to Medicine Sevilla- España 20/06/2022-23/06/2022 open access