Lysophosphatidic Acid Inhibits CD8 T-cell Activation and Control of Tumor Progression

Abstract

CD8 T lymphocytes are able to eliminate nascent tumor cells through a process referred to as immune surveillance. However, multiple inhibitory mechanisms within the tumor microenvironment have been described that impede tumor rejection by CD8 T cells, including increased signaling by inhibitory receptors. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that has been shown repeatedly to promote diverse cellular processes benefiting tumorigenesis. Accordingly, the increased expression of LPA and LPA receptors is a common feature of diverse tumor cell lineages and can result in elevated systemic LPA levels. LPA is recognized by at least 6 distinct G-protein-coupled receptors and several of which are expressed by T cells, although the precise role of LPA signaling in CD8 T cell activation and function has not been defined. Here, we demonstrate that LPA signaling via the LPA5 receptor expressed by CD8 T cells suppresses antigen receptor signaling, cell activation and proliferation in vitro and in vivo. Importantly, in a mouse melanoma model tumor-specific CD8 T cells that are LPA5-deficient are able to control tumor growth significantly better than wild-type tumor-specific CD8 T cells. Together, these data suggest that the production of LPA by tumors serves not only in an autocrine manner to promote tumorigenesis but also as a mechanism to suppress adaptive immunity and highlights a potential novel target for cancer treatment.

Lysophosphatidic Acid Receptor 5 Inhibits B Cell Antigen Receptor Signaling and Antibody Response

“…While attention on LPA has focused on its aberrant production by diverse cancer cell types and its ability to promote tumorigenesis (18, 21, 22), our data suggest that certain malignancies might exploit LPA production not only to promote tumorigenesis but also as a mechanism to inhibit adaptive immune responses (53). In the future it will be important to consider that the pathological or therapeutic settings that alter LPA levels or LPA receptor signaling will also likely modulate adaptive humoral immunity.…”

“…Recently, we have demonstrated that LPA signaling via the LPA 5 receptor expressed by tumor-specific CD8 T cells suppresses tumor immunity (53). Our findings here show that physiological and pathophysiological concentrations of LPA act on the LPA 5 receptor to suppress BCR-mediated calcium release from intracellular stores.…”

Proteome–Metabolome Profiling of Ovarian Cancer Ascites Reveals Novel Components Involved in Intercellular Communication

“…Multiple pieces of evidence point to the involvement of lysophosphatidic acid in the signaling cascades that facilitate the initiation, development, and dissemination of ovarian cancer. Moreover, lysophosphatidic acid induces the formation of inflammatory cytokines, which favor the survival of malignant cells and predetermine their more aggressive behavior (33)(34)(35).…”

Regulation of T Cell Motility In Vitro and In Vivo by LPA and LPA2

“…LPA receptor expression and function on CD8+ T cells has not yet been widely studied. In a recent study Oda et al found that mouse CD8+ T cells express LPA2, 5, and 6 and that LPA5 suppresses CD8+ T cell receptor activation, signaling, and tumor immunity [56]. The CD4+ T cell studies were performed before the identification of the P2Y family of receptors (LPA4–6) and the expression of all of the LPA receptors over the course of T cell activation has not been rigorously examined.…”