Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor
Li Yang, … , David P. Carbone, Richard M. Breyer
Li Yang, … , David P. Carbone, Richard M. Breyer
Published March 1, 2003
Citation Information: J Clin Invest. 2003;111(5):727-735. https://doi.org/10.1172/JCI16492.
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Article Oncology

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

Abstract

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.

Authors

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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Analysis of tumor angiogenesis in EP2–/– and wild-type animals. (a) Stai...
Analysis of tumor angiogenesis in EP2–/– and wild-type animals. (a) Staining of MC26 tumor sections with anti-CD31 Ab. Tumor samples were fixed with 4% paraformaldehyde, embedded in paraffin, and cut and stained using an anti-CD31 Ab. Blood vessels were visualized by the brown color of the CD31-labeled endothelial cells (×400). Slides were lightly counterstained with Mayer’s hematoxylin. (b) VEGF concentration of tumors from EP2–/– and wild-type mice. Tumor tissue lysates were prepared by homogenization. Mouse VEGF was quantitated using ELISA. Data show VEGF production in pg per milligram of tumor proteins. Three mice each of EP2–/– and wild type were used, with triplicates for each sample in the immunoassay.