title: The Toll-like receptor 7/8 agonist resiquimod greatly increases the immunostimulatory capacity of human acute myeloid leukemia cells.
abstract: Immunotherapy for leukemia is a promising targeted strategy to eradicate residual leukemic cells after standard therapy, in order to prevent relapse and to prolong the survival of leukemia patients. However, effective anti-leukemia immune responses are hampered by the weak immunogenicity of leukemic cells. Therefore, much effort is made to identify agents that could increase the immunogenicity of leukemic cells and activate the immune system. Synthetic agonists of Toll-like receptor (TLR)7 and TLR8 are already in use as anticancer treatment, because of their ability to activate several immune pathways simultaneously, resulting in effective antitumor immunity. However, for leukemic cells little is known about the expression of TLR7/8 and the direct effects of their agonists. We hypothesized that TLR7/8 agonist treatment of human acute myeloid leukemia (AML) cells would lead to an increased immunogenicity of AML cells. We observed expression of TLR7 and TLR8 in primary human AML cells and AML cell lines. Passive pulsing of primary AML cells with the TLR7/8 agonist R-848 resulted in increased expression of MHC molecules, production of proinflammatory cytokines, and enhanced allogeneic naïve T cell-stimulatory capacity. These effects were absent or suboptimal if R-848 was administered intracellularly by electroporation. Furthermore, when AML cells were cocultured with allogeneic PBMC in the presence of R-848, interferon (IFN)-gamma was produced by allogeneic NK and NKT cells and AML cells were killed. In conclusion, the immunostimulatory effect of the TLR7/8 agonist R-848 on human AML cells could prove useful for the design of TLR-based immunotherapy for leukemia.
authors.affiliation: Vaccine and Infectious Disease Institute (VIDI), Laboratory of Experimental Hematology, Faculty of Medicine, University of Antwerp, Antwerp, Belgium. evelien.smits@uza.be
authors.forename: Evelien L J M
authors.initials: EL
authors.lastname: Smits
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cools
authors.forename: Eva
authors.initials: E
authors.lastname: Lion
authors.forename: Kirsten
authors.initials: K
authors.lastname: Van Camp
authors.forename: Peter
authors.initials: P
authors.lastname: Ponsaerts
authors.forename: Zwi N
authors.initials: ZN
authors.lastname: Berneman
authors.forename: Viggo F I
authors.initials: VF
authors.lastname: Van Tendeloo
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000328:Adult; D000368:Aged; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D006649:Histocompatibility Antigens / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055611:Natural Killer T-Cells / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000096:biosynthesis; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D006649:Histocompatibility Antigens; D007093:Imidazoles; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; C402365:resiquimod