Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
- PMID: 34788605
- PMCID: PMC8761359
- DOI: 10.1016/j.celrep.2021.110013
Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
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.
Keywords: G protein-coupled receptors; T cells; anti-cancer vaccination; autotaxin; chemorepulsion; immunotherapy; lysophosphatidic acid; melanoma; single-cell RNAseq; tumor microenvironment.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests Z.J. is an employee and shareholder of iOnctura SA, a company developing an ATX inhibitor for use in cancer.
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