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Prostaglandin E₂ Impairs CD4⁺ T Cell Activation by Inhibition of lck: Implications in Hodgkin's Lymphoma

¹ Molecular Tumor Biology and Tumor Immunology, Department of Internal Medicine I, University of Cologne, Cologne, Germany and ² Abramson Cancer Research Center, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Joachim L. Schultze, Molecular Tumor Biology and Tumor Immunology, Department of Internal Medicine I, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany. Phone: 49-221-478-4489; Fax: 49-221-478-5912; E-mail: joachim.schultze{at}uk-koeln.de.

Many tumors, including Hodgkin's lymphoma, are associated with decreased cellular immunity and elevated levels of prostaglandin E₂ (PGE₂), a known inhibitor of CD4⁺ T cell activation, suggested to be involved in immune deviation in cancer. To address the molecular mechanisms tumor-derived PGE₂ might have on primary human CD4⁺ T cells, we used a whole genome-based transcriptional approach and show that PGE₂ severely limited changes of gene expression induced by signaling through the T cell receptor and CD28. This data suggests an interference of PGE₂ at an early step of T cell receptor signaling: indeed, PGE₂ stimulation of T cells leads to inactivation of lck and reduced phosphorylation of ZAP70. Antiapoptotic genes escaped PGE₂-induced inhibition resulting in partial protection from apoptosis in response to irradiation or Fas-mediated signaling. As a functional consequence, PGE₂-treated CD4⁺ T cells are arrested in the cell cycle associated with up-regulation of the cyclin/cyclin-dependent kinase inhibitor p27^kip1. Most importantly, CD4⁺ T cells in Hodgkin's lymphoma show similar regulation of genes that were altered in vitro by PGE₂ in T cells from healthy individuals. These data strongly suggest that PGE₂ is an important factor leading to CD4⁺ T cell impairment observed in Hodgkin's lymphoma. (Cancer Res 2006; 66(2): 1114-22)

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