Secreted autotaxin through LPA suppresses chemotaxis and tumor infiltration of CD8 + T cells

To improve immunotherapy efficacy, a better understanding of the factors that regulate T-cell migration into tumors is essential. Here we uncover a role for autotaxin (ATX) in this process. ATX (encoded by ) produces lysophosphatidic acid (LPA) that activates G protein-coupled receptors (LPAR1-6) to regulate multiple (patho)physiological processes, including tumor progression via LPAR1 and lymphocyte homing via LPAR2. Unexpectedly, we find that melanoma cell-secreted ATX is a major chemorepellent for tumor-infiltrating lymphocytes through Gα-coupled LPAR6, with ATX functioning as an LPA-producing chaperone. Using an anti-cancer vaccination model, we provide proof-of-concept that secreted ATX opposes tumor infiltration of CD8 T cells. Additionally, expression in melanoma tumors correlates with reduced CD8 T-cell infiltration as inferred from single-cell transcriptomics. Hence, by counteracting T-cell infiltration while activating tumor cells via different LPA receptors, the ATX/LPA complex exerts dual actions in the tumor immune microenvironment, which may provide new therapeutic approaches.