Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8(+) T cells

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2021-11-16

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Matas-Rico, Elisa
Frijlink, Elselien
Avila, Irene van der Haar
Menegakis, Apostolos
van Zon, Maaike
Morris, Andrew J.
Koster, Jan
Salgado-Polo, Fernando
de Kivit, Sander
Lanc, Telma

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Cell press
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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 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.

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Lysophosphatidic acid receptor, Lysophospholipase-d, Identification, Exclusion, Pathways, Binding, Microenvironment, Fibroblasts, Metastasis, Chemokines

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