Immunotherapies have demonstrated the utility of targeting the immune system for the eradication of tumors, yet a majority of patients remain refractory to such treatments. Therefore, further advances in our understanding of T-cell activation and inhibitory signals are required to find alternative combinational strategies to treat cancers. Lysophosphatidic acid (LPA) is a bioactive lipid that has been characterized to promote tumor growth via distinct mechanisms and thus displays multiple “hallmarks” of tumorgenesis, including enhancing tumor-promoting inflammation, metastasis, and angiogenesis. Despite LPA receptors (LPARs) being expressed on all immune cells, the impact of LPA on immune cells remains unclear. Work from our lab has previously shown that LPA signals via LPAR5 expressed by CD8+ T-cells to suppress TCR-mediated intracellular calcium mobilization. Thus, we propose that aberrant expression of LPA by diverse tumors serves also to dampen adaptive immune responses, thereby creating an immune suppressive tumor microenvironment. Here, we demonstrate that CD8+ T-cells express three of the six known LPA receptors, and that LPA signaling through LPA5R on CD8+ T-cells has not only a profound inhibition of Ca2+ release after TCR stimulation, but also impedes ERK and Nur77 TCR induced signaling pathway. Importantly we now demonstrate that LPA signaling also decreases the cytolytic function of CD8+ T-cells by inhibiting granule exocytosis. Both adoptive transfer of Lpar5-/- CD8+ T-cells and implantation of tumors into Lpar5-/- hosts leads to greater control of tumor growth, underscoring an immunosuppressive signal mediated by LPA through LPA5R on CD8+ T-cells. Finally, human CD8+ T-cells also express the same LPARs as in the mouse and similarly fail to efficiently release Ca2+ upon TCR stimulation in the presence of LPA. Pharmaceutical inhibition of the human LPA5 receptor restores Ca2+ flux, suggesting a similar mechanism seen in mice. Thus, our data illuminate a novel lipid-receptor interaction that suppresses CD8+ T-cell function in both human and murine cells.
Citation Format: Divij Mathew, Pamela Strauch, Roberta Pelanda, Raul Torres. Lysophosphatidic acid impedes the effector function of CD8+ T-cells through LPA5R [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A202.