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

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

doi:https://doi.org/10.1016/j.celrep.2021.110013

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

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

Research output: Contribution to journal › Article › Academic › peer-review

35 Citations (Scopus)

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.

Original language	English
Article number	110013
Journal	Cell reports
Volume	37
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2021.110013
Publication status	Published - 16 Nov 2021

Keywords

G protein-coupled receptors
T cells
anti-cancer vaccination
autotaxin
chemorepulsion
immunotherapy
lysophosphatidic acid
melanoma
single-cell RNAseq
tumor microenvironment

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https://doi.org/10.1016/j.celrep.2021.110013

Cite this

Matas-Rico, E., Frijlink, E., van der Haar Àvila, I., Menegakis, A., van Zon, M., Morris, A. J., Koster, J., Salgado-Polo, F., de Kivit, S., Lança, T., Mazzocca, A., Johnson, Z., Haanen, J., Schumacher, T. N., Perrakis, A., Verbrugge, I., van den Berg, J. H., Borst, J., & Moolenaar, W. H. (2021). Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells. Cell reports, 37(7), Article 110013. https://doi.org/10.1016/j.celrep.2021.110013

@article{f11ccaf8d860463280b1c170c576f054,

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 = "Elisa Matas-Rico and Elselien Frijlink and {van der Haar {\`A}vila}, Irene and Apostolos Menegakis and {van Zon}, Maaike and Morris, {Andrew J.} and Jan Koster and Fernando Salgado-Polo and {de Kivit}, Sander and Telma Lan{\c c}a and Antonio Mazzocca and Zo{\"e} Johnson and John Haanen and Schumacher, {Ton N.} and Anastassis Perrakis and Inge Verbrugge and {van den Berg}, {Joost H.} and Jannie Borst and Moolenaar, {Wouter H.}",

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 = "https://doi.org/10.1016/j.celrep.2021.110013",

language = "English",

volume = "37",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "7",

}

Matas-Rico, E, Frijlink, E, van der Haar Àvila, I, Menegakis, A, van Zon, M, Morris, AJ, Koster, J, Salgado-Polo, F, de Kivit, S, Lança, T, Mazzocca, A, Johnson, Z, Haanen, J, Schumacher, TN, Perrakis, A, Verbrugge, I, van den Berg, JH, Borst, J & Moolenaar, WH 2021, 'Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells', Cell reports, vol. 37, no. 7, 110013. https://doi.org/10.1016/j.celrep.2021.110013

TY - JOUR

T1 - Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells

AU - Matas-Rico, Elisa

AU - Frijlink, Elselien

AU - van der Haar Àvila, Irene

AU - Menegakis, Apostolos

AU - van Zon, Maaike

AU - Morris, Andrew J.

AU - Koster, Jan

AU - Salgado-Polo, Fernando

AU - de Kivit, Sander

AU - Lança, Telma

AU - Mazzocca, Antonio

AU - Johnson, Zoë

AU - Haanen, John

AU - Schumacher, Ton N.

AU - Perrakis, Anastassis

AU - Verbrugge, Inge

AU - van den Berg, Joost H.

AU - Borst, Jannie

AU - Moolenaar, Wouter H.

N1 - 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 “Ramón y Cajal” Award ( RYC2019-027950-I ) from Ministerio de Ciencia e Innovación (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: © 2021 The Author(s)

PY - 2021/11/16

Y1 - 2021/11/16

N2 - 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.

AB - 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.

KW - G protein-coupled receptors

KW - T cells

KW - anti-cancer vaccination

KW - autotaxin

KW - chemorepulsion

KW - immunotherapy

KW - lysophosphatidic acid

KW - melanoma

KW - single-cell RNAseq

KW - tumor microenvironment

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U2 - https://doi.org/10.1016/j.celrep.2021.110013

DO - https://doi.org/10.1016/j.celrep.2021.110013

M3 - Article

C2 - 34788605

SN - 2211-1247

VL - 37

JO - Cell reports

JF - Cell reports

IS - 7

M1 - 110013

ER -

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

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Keywords

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