title: Adjuvant cationic liposomes presenting MPL and IL-12 induce cell death, suppress tumor growth, and alter the cellular phenotype of tumors in a murine model of breast cancer.
abstract: Dendritic cells (DC) process and present antigens to T lymphocytes, inducing potent immune responses when encountered in association with activating signals, such as pathogen-associated molecular patterns. Using the 4T1 murine model of breast cancer, cationic liposomes containing monophosphoryl lipid A (MPL) and interleukin (IL)-12 were administered by intratumoral injection. Combination multivalent presentation of the Toll-like receptor-4 ligand MPL and cytotoxic 1,2-dioleoyl-3-trmethylammonium-propane lipids induced cell death, decreased cellular proliferation, and increased serum levels of IL-1β and tumor necrosis factor (TNF)-α. The addition of recombinant IL-12 further suppressed tumor growth and increased expression of IL-1β, TNF-α, and interferon-γ. IL-12 also increased the percentage of cytolytic T cells, DC, and F4/80(+) macrophages in the tumor. While single agent therapy elevated levels of nitric oxide synthase 3-fold above basal levels in the tumor, combination therapy with MPL cationic liposomes and IL-12 stimulated a 7-fold increase, supporting the observed cell cycle arrest (loss of Ki-67 expression) and apoptosis (TUNEL positive). In mice bearing dual tumors, the growth of distal, untreated tumors mirrored that of liposome-treated tumors, supporting the presence of a systemic immune response.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute , Houston, Texas 77030, United States.
authors.forename: Ismail M
authors.initials: IM
authors.lastname: Meraz
authors.forename: David J
authors.initials: DJ
authors.lastname: Savage
authors.forename: Victor
authors.initials: V
authors.lastname: Segura-Ibarra
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Li
authors.forename: Jessica
authors.initials: J
authors.lastname: Rhudy
authors.forename: Jianhua
authors.initials: J
authors.lastname: Gu
authors.forename: Rita E
authors.initials: RE
authors.lastname: Serda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000737:chemistry / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism; D008050:Lipid A / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008050:Lipid A; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma; C048436:monophosphoryl lipid A
keywords: Toll-like receptor; breast cancer; interleukin-12; liposome; monophosphoryl lipid A