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

Summary: 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 microen...

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Autores principales:	Elisa Matas-Rico, Elselien Frijlink, Irene van der Haar Àvila, Apostolos Menegakis, Maaike van Zon, Andrew J. Morris, Jan Koster, Fernando Salgado-Polo, Sander de Kivit, Telma Lança, Antonio Mazzocca, Zoë Johnson, John Haanen, Ton N. Schumacher, Anastassis Perrakis, Inge Verbrugge, Joost H. van den Berg, Jannie Borst, Wouter H. Moolenaar
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	lysophosphatidic acid autotaxin chemorepulsion T cells G protein-coupled receptors tumor microenvironment Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/e9e9408a389a42bbba3e0b1045703cf7
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spelling	oai:doaj.org-article:e9e9408a389a42bbba3e0b1045703cf72021-11-18T04:47:56ZAutotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells2211-124710.1016/j.celrep.2021.110013https://doaj.org/article/e9e9408a389a42bbba3e0b1045703cf72021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2211124721014959https://doaj.org/toc/2211-1247Summary: 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.Elisa Matas-RicoElselien FrijlinkIrene van der Haar ÀvilaApostolos MenegakisMaaike van ZonAndrew J. MorrisJan KosterFernando Salgado-PoloSander de KivitTelma LançaAntonio MazzoccaZoë JohnsonJohn HaanenTon N. SchumacherAnastassis PerrakisInge VerbruggeJoost H. van den BergJannie BorstWouter H. MoolenaarElsevierarticlelysophosphatidic acidautotaxinchemorepulsionT cellsG protein-coupled receptorstumor microenvironmentBiology (General)QH301-705.5ENCell Reports, Vol 37, Iss 7, Pp 110013- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	lysophosphatidic acid autotaxin chemorepulsion T cells G protein-coupled receptors tumor microenvironment Biology (General) QH301-705.5
spellingShingle	lysophosphatidic acid autotaxin chemorepulsion T cells G protein-coupled receptors tumor microenvironment Biology (General) QH301-705.5 Elisa Matas-Rico Elselien Frijlink Irene van der Haar Àvila Apostolos Menegakis Maaike van Zon Andrew J. Morris Jan Koster Fernando Salgado-Polo Sander de Kivit Telma Lança Antonio Mazzocca Zoë Johnson John Haanen Ton N. Schumacher Anastassis Perrakis Inge Verbrugge Joost H. van den Berg Jannie Borst Wouter H. Moolenaar Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
description	Summary: 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.
format	article
author	Elisa Matas-Rico Elselien Frijlink Irene van der Haar Àvila Apostolos Menegakis Maaike van Zon Andrew J. Morris Jan Koster Fernando Salgado-Polo Sander de Kivit Telma Lança Antonio Mazzocca Zoë Johnson John Haanen Ton N. Schumacher Anastassis Perrakis Inge Verbrugge Joost H. van den Berg Jannie Borst Wouter H. Moolenaar
author_facet	Elisa Matas-Rico Elselien Frijlink Irene van der Haar Àvila Apostolos Menegakis Maaike van Zon Andrew J. Morris Jan Koster Fernando Salgado-Polo Sander de Kivit Telma Lança Antonio Mazzocca Zoë Johnson John Haanen Ton N. Schumacher Anastassis Perrakis Inge Verbrugge Joost H. van den Berg Jannie Borst Wouter H. Moolenaar
author_sort	Elisa Matas-Rico
title	Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
title_short	Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
title_full	Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
title_fullStr	Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
title_full_unstemmed	Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells
title_sort	autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of cd8+ t cells
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/e9e9408a389a42bbba3e0b1045703cf7
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Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells

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