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

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...

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Detalhes bibliográficos
Autores: Matas-Rico, Elisa, Frijlink, Elselien, van der Haar Àvila, Irene, Menegakis, Apostolos, van Zon, Maaike, Morris, Andrew J., Koster, Jan, Salgado-Polo, Fernando, de Kivit, Sander, Lança, Telma, Mazzocca, Antonio, Johnson, Zoë, Haanen, John, Schumacher, Ton N., Perrakis, Anastassis, Verbrugge, Inge, van den Berg, Joost H., Borst, Jannie, Moolenaar, Wouter H.
Formato: artículo
Fecha de publicación:2021
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18503
Acesso em linha:http://hdl.handle.net/20.500.12105/18503
Access Level:acceso abierto
Palavra-chave:G protein-coupled receptors
T cells
Anti-cancer vaccination
Autotaxin
Chemorepulsion
Immunotherapy
Iysophosphatidic acid
Melanoma
Single-cell RNAseq
Tumor microenvironment
Receptores acoplados a proteínas G
Linfocitos T
Inmunoterapia
Microambiente tumoral
Neoplasias
Células
Animals
CD8-Positive T-Lymphocytes
Cell Line, Tumor
Chemotaxis
Vaccination
Humans
Lymphocytes, Tumor-Infiltrating
Lysophospholipids
Mice
Mice, Inbred C57BL
Phosphoric Diester Hydrolases
Receptors, Lysophosphatidic Acid
Tumor Microenvironment
Descrição
Resumo: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.

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