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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 Gα 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. [Display omitted] • ATX secreted by tumor cells repels TILs and CD8+ T cells ex vivo • LPAR6 qualifies as a T cell migration inhibitory receptor • Tumor-intrinsic ATX suppresses CD8+ T cell infiltration and tumor control in mice • Melanoma single-cell data provides supporting clinical evidence Through LPA production, ATX modulates the tumor microenvironment in autocrine-paracrine manners. Matas-Rico et al. show that ATX/LPA is chemorepulsive for T cells with a dominant inhibitory role for Gα 12/13 -coupled LPAR6. Upon anti-cancer vaccination, tumor-intrinsic ATX suppresses the infiltration of CD8+ T cells without affecting their cytotoxic quality. [ABSTRACT FROM AUTHOR]

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 Gα 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., Competing Interests: Declaration of interests Z.J. is an employee and shareholder of iOnctura SA, a company developing an ATX inhibitor for use in cancer., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)