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

Summary Autotaxin (ATX) is secreted by diverse cell types to produce lysophosphatidic acid (LPA) that regulates multiple biological functions via G protein-coupled receptors LPAR1-6. ATX/LPA promotes tumor cell migration and metastasis mainly via LPAR1; however, its actions in the tumor immune microenvironment remain unclear. Here, we show that ATX secreted by melanoma cells is chemorepulsive for tumor-infiltrating lymphocytes and circulating CD8 + T cells ex vivo , with ATX functioning as an LPA-producing chaperone. Mechanistically, T-cell repulsion predominantly involves G α 12/13 -coupled LPAR6. Upon anti-cancer vaccination of tumor-bearing mice, ATX does not affect the induction of systemic T-cell responses but suppresses tumor infiltration of cytotoxic CD8 + T cells and thereby impairs tumor regression. Moreover, single-cell data from patient samples are consistent with intra-tumor ATX acting as a T-cell repellent. These studies 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.