Journal
CELL REPORTS
Volume 37, Issue 7, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.110013
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Funding
- Dutch Cancer Society [NKI 2013-5951, 10764, NKI 2017-10894]
- German Research Foundation (DFG) [ME 4924/1-1]
- NIH [P30 GM127211]
- Ramon y Cajal'' Award [RYC2019-027950-I]
- Ministerio de Ciencia e Innovacion (MICINN), Spain
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The study reveals that ATX secreted by melanoma cells repels tumor-infiltrating lymphocytes and circulating CD8(+) T cells, acting as a chaperone for LPA. Mechanistically, T cell repulsion is mainly involved G alpha(12/13)-coupled LPAR6, suppressing CD8(+) T cell infiltration and affecting tumor regression.
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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