Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor

Abstract

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.