title: Induction of a CD4+ T regulatory type 1 response by cyclooxygenase-2-overexpressing glioma.
abstract: PGE(2), synthesized by cyclooxygenase-2 (COX-2)-overexpressing tumor, is known to contribute to cellular immune suppression in cancer patients, but the mechanism remains unclear. We report the mechanism of a CD4(+) T regulatory type 1 (Tr1) induction by CD11c(+) mature dendritic cells (DCs) that phagocytose allogeneic and autologous COX-2-overexpressing glioma. A human glioma cell line, U-87MG, and primary cultured glioblastoma cells (MG-377) overexpressed COX-2. We did not detect IL-10Ralpha expression in these gliomas, and rIL-10 did not suppress their COX-2 expression. Exposure to COX-2-overexpressing glioma induced mature DCs to overexpress IL-10 and decreased IL-12p70 production. These DCs induced a Tr1 response, which is characterized by robust secretion of IL-10 and TGF-beta with negligible IL-4 secretion by CD4(+) T cells, and an inhibitory effect on admixed lymphocytes. Peripheral CD4(+) T cell populations isolated from an MG-377 patient also predominantly demonstrated a Tr1 response against MG-377 cells. Selective COX-2 inhibition in COX-2-overexpressing gliomas at the time of phagocytic uptake by DCs abrogated this regulatory response and instead elicited Th1 activity. COX-2 stable transfectants in LN-18 (LN-18-COX2) also induced a Tr1 response. The effect of a COX-2 inhibition in LN-18-COX2 is reversible after administration of PGE(2). Taken together, robust levels of PGE(2) from COX-2-overexpressing glioma, which is unresponsive to IL-10 within the local microenvironment, may cause DCs to secrete high levels of IL-10. These results indicate that COX-2-overexpressing tumors induce a Tr1 response, which is mediated by tumor-exposed, IL-10-enhanced DCs.
authors.affiliation: Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Akasaki
authors.forename: Gentao
authors.initials: G
authors.lastname: Liu
authors.forename: Nancy H C
authors.initials: NH
authors.lastname: Chung
authors.forename: Moneeb
authors.initials: M
authors.lastname: Ehtesham
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: John S
authors.initials: JS
authors.lastname: Yu
mesh_terms: D017209:Apoptosis / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D051546:Cyclooxygenase 2; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007519:Isoantigens / Q000096:biosynthesis; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics*; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins; D010587:Phagocytosis / Q000276:immunology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics*; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics; D053701:Receptors, Interleukin-10; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D007519:Isoantigens; D007527:Isoenzymes; D008565:Membrane Proteins; D018123:Receptors, Interleukin; D053701:Receptors, Interleukin-10; D016753:Interleukin-10; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone