Matas-Rico and Frijlink et al. demonstrated that tumor cell-secreted Autotaxin (ATX; encoded by ENPP2) produced and chaperoned lysophosphatidic acid (LPA), which antagonized the migration of TILs and peripheral blood CD8+ T cells ex vivo, primarily via LPAR6. In a vaccination setting, tumor-intrinsic ATX expression impaired antigen-specific CD8+ T cell infiltration into the tumor and suppressed vaccine-induced tumor control, but did not affect CTL quality or infiltration of CD4+ T cells and Tregs. Single-cell analysis of melanoma tumors revealed a negative correlation between intratumoral ENPP2 expression and CD8+ T cell infiltration.
Contributed by Shishir Pant
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.
Author Info: (1) Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: ematas@uma.es. (2) Division of Tumor Biology and Immunology, Netherlands
Author Info: (1) Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: ematas@uma.es. (2) Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (3) Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (4) Oncode Institute, Utrecht, the Netherlands; Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (5) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (6) Division of Cardiovascular Medicine, Gill Heart Institute and Lexington Veterans Affairs Medical Center, University of Kentucky, Lexington, KY, USA. (7) Laboratory for Experimental Oncology and Radiobiology, Amsterdam UMC, Amsterdam, the Netherlands. (8) Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (9) Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (10) Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (11) Interdisciplinary Department of Medicine, University of Bari School of Medicine, Bari, Italy. (12) iOnctura SA, Campus Biotech Innovation Park, Geneva, Switzerland. (13) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (14) Oncode Institute, Utrecht, the Netherlands; Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (15) Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (16) Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. (17) Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands. (18) Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands. Electronic address: j.g.borst@lumc.nl. (19) Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: w.moolenaar@nki.nl.
