Prostaglandin E2 (PGE2), a major COX metabolite, plays important roles in several facets of tumor biology. We characterized the contribution of the PGE2 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, PGE2 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 PGE2, 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 PGE2-induced inhibition of DC differentiation and function and the diminished antitumor cellular immune responses in vivo.
Li Yang, Noboru Yamagata, Rajwardhan Yadav, Suzanne Brandon, Regina L. Courtney, Jason D. Morrow, Yu Shyr, Mark Boothby, Sebastian Joyce, David P. Carbone, Richard M. Breyer
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