@article{b9de26c64fcd4d24899cc4ea909aab1a,
title = "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",
author = "{van der Haar Avila}, AI and Elselien Frijlink",
note = "Funding Information: We thank Paula Voabil, Jos Urbanus, Yanling Xao, Marjolein Mertz, and Juan Manuel Alba for their help with experiments and data analysis, Kees Franken for making MHC tetramers, Junken Aoki for providing anti-ATX antibodies, and Tomasz Ahrends and Anne van der Leun for helpful discussions and sharing unpublished data. This work was supported by private funding to W.H.M. and grants from the Dutch Cancer Society ( NKI 2013-5951 and 10764 to I.V. and NKI 2017-10894 to J.B. and I.V.), the German Research Foundation (DFG) ( ME 4924/1-1 to A. Mazzocca), and the NIH ( P30 GM127211 to A.J.M.). E.M.-R. is supported by a “Ram{\'o}n y Cajal” Award ( RYC2019-027950-I ) from Ministerio de Ciencia e Innovaci{\'o}n (MICINN), Spain. Funding Information: We thank Paula Voabil, Jos Urbanus, Yanling Xao, Marjolein Mertz, and Juan Manuel Alba for their help with experiments and data analysis, Kees Franken for making MHC tetramers, Junken Aoki for providing anti-ATX antibodies, and Tomasz Ahrends and Anne van der Leun for helpful discussions and sharing unpublished data. This work was supported by private funding to W.H.M. and grants from the Dutch Cancer Society (NKI 2013-5951 and 10764 to I.V. and NKI 2017-10894 to J.B. and I.V.), the German Research Foundation (DFG) (ME 4924/1-1 to A. Mazzocca), and the NIH (P30 GM127211 to A.J.M.). E.M.-R. is supported by a ?Ram?n y Cajal? Award (RYC2019-027950-I) from Ministerio de Ciencia e Innovaci?n (MICINN), Spain. Conceptualization, J.H. Z.J. T.N.S. I.V. J.v.d.B. J.B. and W.H.M.; investigation, E.M.-R. E.F. I.v.d.H.A. A. Menegakis, A. Mazzocca, M.v.Z. A.J.M. J.K. F.S.-P. I.V. and J.v.d.B.; methodology, E.M.-R. E.F. I.v.d.H.A. M.v.Z. A.J.M. J.K. F.S.-P. S.K. T.L. J.H. Z.J. T.N.S. A.P. I.V. J.v.d.B. J.B. and W.H.M; data analysis, E.M.-R. E.F. I.v.d.H.A. A. Menegakis, M.v.Z. A.J.M. J.K. F.S.-P. S.K. T.L. Z.J. A.P. I.V. J.v.d.B. J.B. and W.H.M.; validation, E.M.-R. E.F. I.v.d.H.A. M.v.Z. A.P. I.V. J.v.d.B. and W.H.M.; visualization, E.M.-R. E.F. I.v.d.H.A. A. Menegakis, M.v.Z. J.K. F.S.-P. I.V. and J.B.; writing, E.M.-R. E.F. J.B. and W.H.M.; supervision, J.B. and W.H.M. Z.J. is an employee and shareholder of iOnctura SA, a company developing an ATX inhibitor for use in cancer. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = nov,
day = "16",
doi = "10.1016/j.celrep.2021.110013",
language = "English",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}