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Immunology |
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]
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