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Prevention of Both Direct and Cross-Priming of Antitumor CD8⁺ T-Cell Responses following Overproduction of Prostaglandin E₂ by Tumor Cells In vivo

¹ Department of Cellular and Molecular Medicine, University of Bristol, School of Medical Sciences and ² Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, Bristol, United Kingdom

Requests for reprints: David J. Morgan, School of Medical Sciences, University of Bristol, University Walk, Bristol BS8 1TD, United Kingdom. Phone: 44-117-3312021; Fax: 44-117-9287896; E-mail: d.j.morgan{at}bristol.ac.uk.

Key Words: CD8⁺ T-cell responses • tumor cells • COX-2 • PGE₂ • antigen presentation • cross-presentation • dendritic cells • peripheral tolerance

Defects in antitumor immune responses have been associated with increased release of prostaglandin E₂ (PGE₂) as a result of overexpression of cyclooxygenase (COX)-2 by tumors. In this report, we examine the effects of PGE₂ on antitumor CD8⁺ T-cell responses generated both by cross-presenting dendritic cells and by direct priming by tumor cells. Our data show that PGE₂ inhibits dendritic cell maturation, resulting in the abortive activation of naive CD8⁺ T cells, and is dependent on interleukin-10 production by dendritic cells. Interaction of tumor cells with naïve CD8⁺ T cells in the presence of PGE₂ in vitro results in the induction of CD8⁺ CD28^– T cells, which fail to proliferate or exhibit effector function. In vivo, overexpression of COX-2 by tumor cells results in a decrease in number of tumor-infiltrating dendritic cells and confers the ability of tumor cells to metastasize to the tumor draining lymph nodes. [Cancer Res 2008;68(18):7520–9]