title: Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists.
abstract: This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLA-DR and CD86 expression of AML cells was observed by addition of TNF-α, LPS, R848 alone or combinations. Induced CD80 expression of AML cells was significantly higher through the combination of TNF-α, LPS and R848 (T + L + R) than that by T alone. CTL induced from T + L + R, T + R, T + L, L + R and R, but not T, L alone stimulated cultures showed significantly higher IFN-γ release than the medium control in response to autologous AML cells. IFN-γ release by T + L + R was significantly higher than T or L alone, and T + R was significantly higher than T alone. CTL generated from T + L + R, T + L, T + R, L + R and L alone exerted significantly higher AML cell killing than medium control. AML cell killing by T + L + R and T + R was significantly higher than T or R alone. These results indicate that the combination of T + L + R induces a significantly enhanced antigen presentation effect of AML-DC. We speculate that the complementary effects of reagent combinations may better address the heterogeneity of responses to any single agent in AML cells from different patients.
authors: Division of Blood and Marrow Transplantation, Departments of Medicine, Pathology and the Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, CA, 92093-0960, USA.
authors: RuiKun
authors: R
authors: Zhong
authors: Hongying
authors: H
authors: Li
authors: Karen
authors: K
authors: Messer
authors: Thomas A
authors: TA
authors: Lane
authors: Jiehua
authors: J
authors: Zhou
authors: Edward D
authors: ED
authors: Ball
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists* / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D007093:Imidazoles; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors; D007371:Interferon-gamma; C402365:resiquimod