title: Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro.
abstract: Evasion of apoptosis is a hallmark of cancer cells. Inhibitor of apoptosis proteins (IAPs) act as endogenous inhibitors of programmed cell death and are overexpressed in several tumors including Hodgkin lymphoma (HL). Preclinical studies indicate antitumor activity of IAP antagonists and clinical studies in hematological malignancies are underway. Here, we investigate the impact of the small molecule IAP antagonist LCL161 on HL cell lines. Although the antagonist caused rapid degradation of cIAP1 leading to TNFα secretion, LCL161 did not promote apoptosis significantly. However, LCL161 induced expression of MICA and MICB, ligands for the activating immune receptor NKG2D, and enhanced the susceptibility of HL cells to NKG2D-dependent lysis by NK cells. MICA/B upregulation was dependent on activation of the DNA damage response upon LCL161 treatment. Taken together, we demonstrate a novel link between IAP inhibition, DNA damage and immune recognition.
authors.forename: Maike
authors.initials: M
authors.lastname: Sauer
authors.forename: Katrin S
authors.initials: KS
authors.lastname: Reiners
authors.forename: Hinrich P
authors.initials: HP
authors.lastname: Hansen
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.forename: Stephan
authors.initials: S
authors.lastname: Gasser
authors.forename: Elke Pogge
authors.initials: EP
authors.lastname: von Strandmann
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006689:Hodgkin Disease / Q000276:immunology / Q000503:physiopathology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C527085:KLRK1 protein, human; C574246:LCL161; D055655:NK Cell Lectin-Like Receptor Subfamily K; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha