Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4-1BBL.
Recently, gene-based cytokine treatment has been actively pursued as a new promising approach in treating cancer. In an effort to augment the efficiency of antitumor effect by cytokine-mediated immunotherapy, we selected both interleukin (IL)-12 and 4-1BB ligand (4-1BBL) as suitable cytokines to fully activate the type-1 immune response. Coexpression of IL-12 and 4-1BBL mediated by oncolytic adenovirus (Ad) greatly enhanced the antitumor effect. Further, synergistic enhancement in interferon (IFN)-gamma levels were seen in mice treated with oncolytic Ad expressing both IL-12 and 4-1BBL. Next, to improve the overall antitumor immune response, we coadministered IL-12- and 4-1BBL-coexpressing oncolytic Ad with dendritic cells (DCs). Combination treatment of IL-12- and 4-1BBL-coexpressing oncolytic Ad and DCs elicited greater antitumor and antimetastatic effects than either treatment alone. Moreover, enhanced type-1 antitumor immune response and higher migratory abilities of DCs in tumors were also observed in the combination arms. The nature of the enhanced antitumor immune response seems to be mediated through the enhanced cytolytic activity of cytotoxic T lymphocytes (CTLs) and IFN-gamma-releasing immune cells. Taken together, these data highlight the potential therapeutic benefit of combining IL-12- and 4-1BBL-coexpressing oncolytic Ad with DCs and warrants further evaluation in the clinic.
Huang
Jing-Hua
JH
Brain Korea 21 Project for Medical Sciences, Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
Zhang
Song-Nan
SN
Choi
Kyung-Ju
KJ
Choi
Il-Kyu
IK
Kim
Joo-Hang
JH
Lee
Min-Geol
MG
Lee
Mingul
M
Kim
Hoguen
H
Yun
Chae-Ok
CO
D053330:4-1BB Ligand / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D008545:Melanoma / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*
D053330:4-1BB Ligand; D018664:Interleukin-12