title: Intrapulmonary Delivery of CpG Microparticles Eliminates Lung Tumors.
abstract: CpG oligonucleotides (ODN) stimulate the innate immune system by triggering cells that express TLR9. The resulting response promotes tumor regression, an effect optimized by delivery of CpG ODN to the tumor site. This work examines the effect of instilling CpG ODN adsorbed onto polyketal microparticles (CpG-MP) into the lungs of mice with non-small cell lung cancer. Intrapulmonary delivery of CpG-MP improved ODN uptake and retention at the tumor site, thereby inducing a stronger Th1 response than systemically administered or unadsorbed CpG ODN. CpG-MP reversed the immunosuppression that characterized the tumor microenvironment by (i) decreasing the number of immunosuppressive Tregs and M2 macrophages while (ii) increasing the number of tumoricidal CD8(+) T cells and M1 macrophages. These effects promoted tumor regression and culminated in 82% permanent survival of mice with otherwise fatal Lewis lung cancer.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland. Graduate School of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Graduate School of Agriculture, Shinshu University, Nagano, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimosato
authors.affiliation: Graduate School of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan.
authors.forename: Atsuhisa
authors.initials: A
authors.lastname: Ueda
authors.affiliation: Graduate School of Internal Medicine and Clinical Immunology, Yokohama City University, Yokohama, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishigatsubo
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland. klinmand@mail.nih.gov.
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D002214:Capsules; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D007113:Immunity, Innate / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002214:Capsules; C583868:CpG ODN 1555; D009838:Oligodeoxyribonucleotides