Delivery of dendritic cells engineered to secrete IFN-alpha into central nervous system tumors enhances the efficacy of peripheral tumor cell vaccines: dependence on apoptotic pathways.
We tested whether modulation of the CNS-tumor microenvironment by delivery of IFN-alpha-transduced dendritic cells (DCs: DC-IFN-alpha) would enhance the therapeutic efficacy of peripheral vaccinations with cytokine-gene transduced tumor cells. Mice bearing intracranial GL261 glioma or MCA205 sarcoma received peripheral immunizations with corresponding irradiated tumor cells engineered to express IL-4 or GM-CSFs, respectively, as well as intratumoral delivery of DC-IFN-alpha. This regimen prolonged survival of the animals and induced tumor-specific CTLs that expressed TRAIL, which in concert with perforin and Fas ligand (FasL) was involved in the tumor-specific CTL activity of these cells. The in vivo antitumor activity associated with this approach was abrogated by administration of neutralizing mAbs against TRAIL or FasL and was not observed in perforin-/-, IFN-gamma-/-, or FasL-/- mice. Transduction of the tumor cells with antiapoptotic protein cellular FLIP rendered the gene-modified cells resistant to TRAIL- or FasL-mediated apoptosis and to CTL killing activity in vitro. Furthermore, the combination therapeutic regimen was ineffective in an intracranial cellular FLIP-transduced MCA205 brain tumor model. These results suggest that the combination of intratumoral delivery of DC-IFN-alpha and peripheral immunization with cytokine-gene transduced tumor cells may be an effective therapy for brain tumors that are sensitive to apoptotic signaling pathways.
Kuwashima
Naruo
N
Department of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213, USA.
Nishimura
Fumihiko
F
Eguchi
Junichi
J
Sato
Hidemitsu
H
Hatano
Manabu
M
Tsugawa
Takahiko
T
Sakaida
Tsukasa
T
Dusak
Jill E
JE
Fellows-Mayle
Wendy K
WK
Papworth
Glenn D
GD
Watkins
Simon C
SC
Gambotto
Andrea
A
Pollack
Ian F
IF
Storkus
Walter J
WJ
Okada
Hideho
H
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics; D019264:Adoptive Transfer; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000276:immunology*; D001932:Brain Neoplasms / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000502:physiology / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation*; D005910:Glioma / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control; D015552:Injections, Intralesional; D007276:Injections, Intraventricular; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*; D014161:Transduction, Genetic
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016207:Cytokines; D016898:Interferon-alpha