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.

• Authors: Shannon K Oda, Pamela Strauch, Yuko Fujiwara, Amin Al-Shami, Tamas Oravecz, Gabor Tigyi, Roberta Pelanda, Raul M Torres
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 1 Issue 4 Pg. 245-55 (Oct 2013) ISSN: 2326-6074 [Electronic] United States
• PMID: 24455753 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• Receptors, Lysophosphatidic Acid
• lysophosphatidic acid

Topics

• Animals
• CD8-Positive T-Lymphocytes (immunology)
• Carcinogenesis
• Cell Line, Tumor
• Immunologic Surveillance (drug effects)
• Lymphocyte Activation
• Lysophospholipids (metabolism)
• Melanoma (drug therapy)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplastic Processes
• Receptors, Lysophosphatidic Acid (metabolism)
• Signal Transduction