title: Effective immunotherapy against murine gliomas using type 1 polarizing dendritic cells--significant roles of CXCL10.
abstract: In an attempt to develop effective vaccines against central nervous system (CNS) tumors, we evaluated the ability of vaccines with standard dendritic cells (DC) versus type 1 polarizing DCs (DC1) to induce glioma-specific type 1 CTLs with CNS tumor-relevant homing properties and the mechanism of their action. C57BL/6 mouse-derived bone marrow cells were cultured with mouse granulocyte/macrophage colony-stimulating factor (GM-CSF) for 6 days, and CD11c(+) cells were subsequently cultured with GM-CSF, rmIFN-gamma, rmIFN-alpha, rmIL-4, and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose for 24 hours to generate DC1s. In analogy to their human counterparts, mouse DC1s exhibited surface marker profiles of mature DCs and produced high levels of IL-12 and CXCL10. Importantly for their application as cancer vaccines, such DC1s stably retained their type 1 phenotype even when exposed to type 2-promoting or regulatory T cell (Treg)-promoting environments. Consistently, mouse DC1s induced antigen-specific type 1 CTLs more efficiently than nonpolarized DCs in vitro. DC1s given s.c. migrated into draining lymph nodes, induced antigen-specific CTLs, and suppressed Treg accumulation. In addition, s.c. immunization with DC1s loaded with glioma-associated antigen (GAA)-derived CTL epitope peptides prolonged the survival of CNS GL261 glioma-bearing mice, which was associated with efficient CNS glioma homing of antigen-specific CTLs. Intratumoral injections of GAA peptide-loaded DC1s further enhanced the anti-CNS glioma effects of DC1-based s.c. immunization. Interestingly, the antitumor functions were abrogated with CXCL10(-/-) mouse-derived DC1s. Collectively, these findings show the anti-CNS glioma effects of DC1-based therapy and a novel role of CXCL10 in the immunologic and therapeutic activity of DC-based cancer vaccines.
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhu
authors.forename: Ryo
authors.initials: R
authors.lastname: Ueda
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sasaki
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.forename: Heather A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Gibson
authors.forename: Simon C
authors.initials: SC
authors.lastname: Watkins
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Muthuswamy
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D000818:Animals; D015415:Biomarkers; D023201:CD40 Ligand / Q000276:immunology; D019496:Cancer Vaccines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D016543:Central Nervous System Neoplasms / Q000276:immunology* / Q000473:pathology; D054357:Chemokine CXCL10 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005434:Flow Cytometry; D005910:Glioma / Q000276:immunology* / Q000473:pathology; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013945:Thymoma / Q000276:immunology
chemical_list: D015415:Biomarkers; D019496:Cancer Vaccines; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D023201:CD40 Ligand