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

<jats:title>Abstract</jats:title><jats:p>CD8 T lymphocytes are able to eliminate nascent tumor cells through a process referred to as immunosurveillance. 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 exaggerated 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 six distinct G protein–coupled receptors, several of which are expressed by T cells, although the precise function of LPA signaling in CD8 T-cell activation and function has not been defined. Here, we show 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. Cancer Immunol Res; 1(4); 245–55. ©2013 AACR.</jats:p>