Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor.
Prostaglandin E(2) (PGE(2)), a major COX metabolite, plays important roles in several facets of tumor biology. We characterized the contribution of the PGE(2) EP2 receptor to cancer-associated immune deficiency using EP2(-/-) mice. EP2(-/-) mice exhibited significantly attenuated tumor growth and longer survival times when challenged with MC26 or Lewis lung carcinoma cell lines as compared with their wild-type littermates. While no differences in T cell function were observed, PGE(2) suppressed differentiation of DCs from wild-type bone marrow progenitors, whereas EP2-null cells were refractory to this effect. Stimulation of cells in mixed lymphocyte reactions by wild-type DCs was suppressed by treatment with PGE(2), while EP2(-/-)-derived DCs were resistant to this effect. In vivo, DCs, CD4(+), and CD8(+) T cells were significantly more abundant in draining lymph nodes of tumor-bearing EP2(-/-) mice than in tumor-bearing wild-type mice, and a significant antitumor cytotoxic T lymphocyte response could be observed only in the EP2(-/-) animals. Our data demonstrate an important role for the EP2 receptor in PGE(2)-induced inhibition of DC differentiation and function and the diminished antitumor cellular immune responses in vivo.
Yang
Li
L
Department of Medicine, The Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Yamagata
Noboru
N
Yadav
Rajwardhan
R
Brandon
Suzanne
S
Courtney
Regina L
RL
Morrow
Jason D
JD
Shyr
Yu
Y
Boothby
Mark
M
Joyce
Sebastian
S
Carbone
David P
DP
Breyer
Richard M
RM
D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D015232:Dinoprostone / Q000494:pharmacology; D005260:Female; D007153:Immunologic Deficiency Syndromes / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000209:etiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D018078:Receptors, Prostaglandin E / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D013601:T-Lymphocytes / Q000276:immunology; D014407:Tumor Cells, Cultured
C545645:Ptger2 protein, mouse; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone