title: Optimizing DC vaccination by combination with oncolytic adenovirus coexpressing IL-12 and GM-CSF.
abstract: Dendritic cell (DC)-based vaccination is a promising strategy for cancer immunotherapy. However, clinical trials have indicated that immunosuppressive microenvironments induced by tumors profoundly suppress antitumor immunity and inhibit vaccine efficacy, resulting in insufficient reduction of tumor burdens. To overcome these obstacles and enhance the efficiency of DC vaccination, we generated interleukin (IL)-12- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-coexpressing oncolytic adenovirus (Ad-ΔB7/IL12/GMCSF) as suitable therapeutic adjuvant to eliminate immune suppression and promote DC function. By treating tumors with Ad-ΔB7/IL12/GMCSF prior to DC vaccination, DCs elicited greater antitumor effects than in response to either treatment alone. DC migration to draining lymph nodes (DLNs) dramatically increased in mice treated with the combination therapy. This result was associated with upregulation of CC-chemokine ligand 21 (CCL21(+)) lymphatics in tumors treated with Ad-ΔB7/IL12/GMCSF. Moreover, the proportion of CD4(+)CD25(+) T-cells and vascular endothelial growth factor (VEGF) expression was decreased in mice treated with the combination therapy. Furthermore, combination therapy using immature DCs also showed effective antitumor effects when combined with Ad-ΔB7/IL12/GMCSF. The combination therapy had a remarkable therapeutic efficacy on large tumors. Taken together, oncolytic adenovirus coexpressing IL-12 and GM-CSF in combination with DC vaccination has synergistic antitumor effects and can act as a potent adjuvant for promoting and optimizing DC vaccination.
authors.affiliation: Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seodaemun-Gu, Seoul, Korea.
authors.forename: Song-Nan
authors.initials: SN
authors.lastname: Zhang
authors.forename: Il-Kyu
authors.initials: IK
authors.lastname: Choi
authors.forename: Jing-Hua
authors.initials: JH
authors.lastname: Huang
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Kyung-Ju
authors.initials: KJ
authors.lastname: Choi
authors.forename: Chae-Ok
authors.initials: CO
authors.lastname: Yun
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D054421:Chemokine CCL21 / Q000096:biosynthesis; D003131:Combined Modality Therapy / Q000379:methods; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D018664:Interleukin-12 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology; D008545:Melanoma / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050504:Oncolytic Viruses / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014611:Vaccination; D014612:Vaccines; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D019496:Cancer Vaccines; D054421:Chemokine CCL21; D053645:Interleukin-2 Receptor alpha Subunit; D014612:Vaccines; D042461:Vascular Endothelial Growth Factor A; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor