title: Generating CTLs against the subdominant EBV LMP antigens by transient expression of an A20 inhibitor with EBV LMP proteins in human DCs.
abstract: Epstein-Barr virus (EBV) infection leads to Hodgkin's disease (HD) in some immunocompetent hosts. The malignant Reed-Sternberg cells of HD only express a limited array of subdominant EBV antigens to evade pre-existing immune responses to EBV. The EBV-encoded latent membrane proteins (LMP1 and LMP2), which are expressed by HD and various EBV-associated malignancies, have been proposed as a potential target for cytotoxic T lymphocyte (CTL)-based therapy. However, the precursor frequency for LMP-specific CTL is generally low in healthy EBV-infected hosts, and immunotherapy based on these antigens is often compromised by the poor immunogenicity and the oncogenic potential. In the present study, we report that transiently expressing an inhibitor of A20, a key negative regulator of inflammatory signaling pathways, together with the LMP antigens (truncated LMP1 and full-length LMP2) greatly enhances maturation and cytokine production of human (h) monocyte-derived dendritic cells (DCs). As a consequence, LMP1/2-expressed, A20-silenced hDCs have an enhanced potency to prime LMP-specific T-cell response. When the in vitro primed T cells are adoptively transferred into tumor-xenografted, severe-combined immunodeficient mice, some of the xenografted tumors approach complete regression. Thus, the study may provide an available resource of LMP-specific T cells for T-cell immunotherapy.
authors: Norris Comprehensive Cancer Center, Department of Microbiology and Immunology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors: B
authors: B
authors: Hong
authors: G
authors: G
authors: Peng
authors: L
authors: L
authors: Berry
authors: S
authors: S
authors: Gottschalk
authors: J U
authors: JU
authors: Jung
authors: S-Y
authors: SY
authors: Chen
authors: X F
authors: XF
authors: Huang
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation; D008228:Lymphoma, Non-Hodgkin / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014763:Viral Matrix Proteins / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D014763:Viral Matrix Proteins; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3