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)