LPA5 Is an Inhibitory Receptor That Suppresses CD8 T-Cell Cytotoxic Function via Disruption of Early TCR Signaling

Abstract

Persistent T cell antigen receptor (TCR) signaling by CD8 T cells is a feature of cancer and chronic infections and results in the sustained expression of, and signaling by, inhibitory receptors, which ultimately impair cytotoxic activity via poorly characterized mechanisms. We have previously determined that the LPA 5 GPCR expressed by CD8 T cells, upon engaging the lysophosphatidic acid (LPA) bioactive serum lipid, functions as an inhibitory receptor able to negatively regulate TCR signaling. Notably, the levels of LPA and autotaxin (ATX), the phospholipase D enzyme that produces LPA, are often increased in chronic inflammatory disorders such as chronic infections, autoimmune diseases, obesity, and cancer. In this report, we demonstrate that LPA engagement selectively by LPA 5 on human and mouse CD8 T cells leads to the inhibition of several early TCR signaling events including intracellular calcium mobilization and ERK activation. We further show that, as a consequence of LPA 5 suppression of TCR signaling, the exocytosis of perforin-containing granules is significantly impaired and reflected by repressed in vitro and in vivo CD8 T cell cytolytic activity. Thus, these data not only document LPA 5 as a novel inhibitory receptor but also determine the molecular and biochemical mechanisms by which a naturally occurring serum lipid that is elevated under settings of chronic inflammation signals to suppress CD8 T cell killing activity in both human and murine cells. As diverse tumors have repeatedly been shown to aberrantly produce LPA that acts in an autocrine manner to promote tumorigenesis, our findings further implicate LPA in activating a novel inhibitory receptor whose signaling may be therapeutically silenced to promote CD8 T cell immunity.

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

“…This defines LPAR6 as an inducible receptor whose regulation is currently unknown. Although LPAR4 and LPAR5 were not expressed in ex vivo expanded TILs, the latter receptor is nonetheless of immunooncological importance since its genetic deletion in mice enhances T-cell receptor activity and anti-tumor responses (Mathew et al, 2019). Studies using Lpar5(-/-/Lpar6(-/-) doubleknockout mice should aid to elucidate the combined actions of these non-EDG LPA receptors on T-cell migratory behavior and anti-tumor efficacy.…”

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…In addition, chronic LPA signaling enables cancer cells to evade the immune system [30,32,70]. Recent work shows that this involves increased signaling through LPAR5 on CD8+ T-cells and blocking of T-cell antigen receptor responses [71]. LPA also increases vascular endothelial growth factor (VEGF) production, which stimulates the angiogenesis needed for tumor growth [72].…”

A Novel Therapeutic Reagent, KA-1002 for Alleviating Lysophosphatidic Acid-Mediated Inflammation Related Gene Expression in Swine Macrophages

“…A potent endogenous inflammatory molecule, LPA triggers a broad range of inflammatory responses, and has multiple synthesis routes in various environmental stress associated conditions [17][18][19][20][21][22]. Although LPA is a well-known endogenous molecule for inflammatory diseases [15][16][17][18][19][20][21][22], the effect of LPA on swine macrophages and the molecular mechanism for pathogenesis of LPA on swine are not fully understood until now. LPA is well known for its pathological functions in various inflammatory diseases, such as cancers and respiratory diseases suggesting a reasonable involvement of LPA in chronic/acute inflammatory disorders illnesses [15][16][17].…”

“…Although LPA is a well-known endogenous molecule for inflammatory diseases [15][16][17][18][19][20][21][22], the effect of LPA on swine macrophages and the molecular level mechanism for pathogenesis of LPA on swine are not fully understood until now. Thus, the investigation about the LPA mediated inflammatory condition in swine macrophages should be helpful for understanding the therapeutic mechanism of LPA-antagonistic therapeutics on porcine inflammatory diseases related abnormally upregulated LPA condition.…”