title: Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL.
abstract: BCG, the current gold standard immunotherapy for bladder cancer, exerts its activity via recruitment of neutrophils to the tumor microenvironment. Many patients do not respond to BCG therapy, indicating the need to understand the mechanism of action of BCG-stimulated neutrophils and to identify ways to overcome resistance to BCG therapy. Using isolated human neutrophils stimulated with BCG, we found that TNF-α is the key mediator secreted by BCG-stimulated neutrophils. RT4v6 human bladder cancer cells, which express TNFR1, CD95/Fas, CD95 ligand/FasL, DR4, and DR5, were resistant to BCG-stimulated neutrophil conditioned medium but effectively killed by the combination of conditioned medium and Smac mimetic. rhTNF-α and rhFasL, but not rhTRAIL, in combination with Smac mimetic, generated signature molecular events similar to those produced by BCG-stimulated neutrophils in combination with Smac mimetic. However, experiments using neutralizing antibodies to these death ligands showed that TNF-α secreted from BCG-stimulated neutrophils was the key mediator of anticancer action. These findings explain the mechanism of action of BCG and identified Smac mimetics as potential combination therapeutic agents for bladder cancer.
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Goodwin
authors.initials: G
authors.lastname: Jinesh G
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chunduru
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
mesh_terms: D015153:Blotting, Western; D049109:Cell Proliferation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D018716:Molecular Mimicry; D009163:Mycobacterium bovis / Q000276:immunology*; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D009842:Oligopeptides / Q000494:pharmacology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D017077:Culture Media, Conditioned; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D009842:Oligopeptides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C532637:SMAC peptide; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha