Aberrant tumor derived LPA production suppresses CD8+ T cells though the LPA5R to promote tumor growth.

Abstract

Abstract As a bioactive signaling lipid, lysophosphatidic acid (LPA) is in the same phospholipid family as sphingosine-1-phosphate (S1P) yet its impact on immune cells remains unclear, despite that all immune cells express specific LPA receptors. Generated systemically through the extracellular enzyme Autotaxin, LPA exerts its biological influence through 6 known G protein couple receptors (GPCRs), LPAR1-6. Aberrant LPA production has been linked to multiple “hallmarks” of tumorigenesis, including enhancing tumor promoting inflammation, metastasis, and angiogenesis. We propose that up regulation of tumor-derived LPA can also dampen adaptive immune responses, thereby creating an immune suppressive tumor microenvironment. CD8+ T cells are known to be able to eliminate nascent tumors, yet over time are often rendered functionally silent due to tumor-derived signals that act on inhibitory receptors such as CTLA4 and PD1. Work from our lab has found that pathological levels of LPA can also dampen TCR signaling suggesting an additional mechanism by which cancers avoid elimination. Strikingly, ablation of LPAR5 on CD8+ T cells significantly reduced tumor burden compared to wild type CD8+ T cells, suggesting that LPAR5 is a novel inhibitory lipid receptor. Given the recent success of checkpoint blockade therapy for the treatment of cancers, we are currently characterizing this novel inhibitory interaction between CD8+ T cells and LPA generated in the tumor microenvironment.