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

Abstract

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

Immunologic pathomechanism of Hodgkin's lymphoma

“…TARC (CCL17), IL-13, CD80, CD86, and CD40-CD40L interactions all contribute to the formation of tumor infiltrating T cells. HRS cells also produce some immunosuppressive factors (IL-10, TGF-b, galectin-1, and prostaglandin E2) [69][70][71], whereas CD95/FAS ligand expressed by HRS cells stimulate the apoptosis of activated Th1 and CD8 þ T cells. Tregs also produce IL-10, which indirectly contributes to the protection against cytotoxic T and NK cells [63].…”

Increased Antigen Cross-Presentation but Impaired Cross-Priming after Activation of Peroxisome Proliferator-Activated Receptor γ Is Mediated by Up-Regulation of B7H1

“…RNA isolation and quantification were performed as described previously (25). cRNA (1.5 g) was hybridized to BeadChip Arrays (MouseWG-6 v2 Expression BeadChip; Illumina) and scanned on Illumina BeadStation 500 X.…”

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

“…Macrophages in patients with Hodgkin's lymphoma highly produce PGE 2 , which can suppress cell-mediated immunity [30,31]. In a small study, Hazar et al demonstrated that in 70% of Hodgkin's patients' HRS cells expressed Cox-2 [32].…”