Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression.
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.
Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado.
Shannon K
SK
Oda
Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado.
Pamela
P
Strauch
Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, Tennessee.
Yuko
Y
Fujiwara
Lexicon Pharmaceuticals, Woodlands, Texas.
Amin
A
Al-Shami
Lexicon Pharmaceuticals, Woodlands, Texas.
Tamas
T
Oravecz
Department of Physiology, University of Tennessee Health Science Center Memphis, Memphis, Tennessee.
Gabor
G
Tigyi
Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado.
Roberta
R
Pelanda
Integrated Department of Immunology, University of Colorado Denver and National Jewish Health, Denver, Colorado.
Raul M
RM
Torres
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D007157:Immunologic Surveillance / Q000187:drug effects; D008213:Lymphocyte Activation; D008246:Lysophospholipids / Q000378:metabolism*; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009385:Neoplastic Processes; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D015398:Signal Transduction
D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid
CD8 T cells; GPR92; LPA5; Lysophosphatidic acid; melanoma