title: Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth.
abstract: Generating antitumor responses through the inhibition of tumor-derived immune suppression represents a promising strategy in the development of cancer immunotherapeutics. Here, we present a strategy incorporating delivery of the bacterium Salmonella typhimurium (ST), naturally tropic for the hypoxic tumor environment, transformed with a small hairpin RNA (shRNA) plasmid against the immunosuppressive molecule indoleamine 2,3-dioxygenase 1 (shIDO). When systemically delivered into mice, shIDO silences host IDO expression and leads to massive intratumoral cell death that is associated with significant tumor infiltration by polymorphonuclear neutrophils (PMN). shIDO-ST treatment causes tumor cell death independently of host IDO and adaptive immunity, which may have important implications for use in immunosuppressed patients with cancer. Furthermore, shIDO-ST treatment increases reactive oxygen species (ROS) produced by infiltrating PMNs and, conversely, PMN immunodepletion abrogates tumor control. Silencing of host IDO significantly enhances S. typhimurium colonization, suggesting that IDO expression within the tumor controls the immune response to S. typhimurium. In summary, we present a novel approach to cancer treatment that involves the specific silencing of tumor-derived IDO that allows for the recruitment of ROS-producing PMNs, which may act primarily to clear S. typhimurium infection, but in the process also induces apoptosis of surrounding tumor tissue resulting in a vigorous antitumor effect.
authors.affiliation: Department of Virology, Division of Translational Vaccine Research, City of Hope, Duarte, California, USA.
authors.forename: Céline A
authors.initials: CA
authors.lastname: Blache
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Manuel
authors.forename: Teodora I
authors.initials: TI
authors.lastname: Kaltcheva
authors.forename: Andrea N
authors.initials: AN
authors.lastname: Wong
authors.forename: Joshua D I
authors.initials: JD
authors.lastname: Ellenhorn
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015169:Colony Count, Microbial; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D030781:Organisms, Genetically Modified; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000235:genetics* / Q000254:growth & development* / Q000276:immunology / Q000502:physiology; D014169:Transformation, Bacterial / Q000502:physiology
chemical_list: C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D034741:RNA, Small Interfering