title: Sensitization of IL-2 signaling through TLR-7 enhances B lymphoma cell immunogenicity.
abstract: The innate ability of B lymphoma cells to escape control by tumor-reactive T cells must be overcome to develop effective immunotherapies for these diseases. Because signals from both the innate and adaptive immune systems direct the acquisition of strong immunogenicity by professional APCs, the effects of IL-2 and the TLR-7 agonist, S28690, on the immunogenic properties of chronic lymphocytic leukemia (CLL) B cells were studied. IL-2 with S28690 caused CLL cells to proliferate and increased their expression of B7-family members, production of TNF-alpha and IL-10, and levels of tyrosine-phosphorylated STAT-1 and STAT-3 proteins. S28690 increased CD25 expression on CLL cells and sensitized them to IL-2 signaling. However, IL-2 did not change TLR-7 expression or signaling in CLL cells. The ability to stimulate T cell proliferation required additional activation of protein kinase C, which inhibited tumor cell proliferation, "switched off" IL-10 production, and caused essentially all CLL cells (regardless of clinical stage) to acquire a CD83(high)CD80(high)CD86(high)CD54(high) surface phenotype marked by the activation of STAT-1 without STAT-3. These findings suggest that TLR-7 "licenses" human B cells to respond to cytokines of the adaptive immune system (such as IL-2) and provide a strategy to increase the immunogenicity of lymphoma cells for therapeutic purposes.
authors.affiliation: Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Jelena
authors.initials: J
authors.lastname: Tomic
authors.forename: Dionne
authors.initials: D
authors.lastname: White
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Shi
authors.forename: Jenny
authors.initials: J
authors.lastname: Mena
authors.forename: Caitlin
authors.initials: C
authors.lastname: Hammond
authors.forename: Liwei
authors.initials: L
authors.lastname: He
authors.forename: Richard L
authors.initials: RL
authors.lastname: Miller
authors.forename: David E
authors.initials: DE
authors.lastname: Spaner
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011493:Protein Kinase C / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology; D015375:Receptors, Interleukin-2 / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000276:immunology* / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D007376:Interleukin-2; D011804:Quinolines; D015375:Receptors, Interleukin-2; C508708:S 28690; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051199:Toll-Like Receptor 7; D011493:Protein Kinase C