Delivery of interferon-alpha transfected dendritic cells into central nervous system tumors enhances the antitumor efficacy of peripheral peptide-based vaccines.
We evaluated the effects, on immunity and survival, of injection of interferon (IFN)-alpha-transfected dendritic cells (DC-IFN-alpha) into intracranial tumors in mice immunized previously with syngeneic dendritic cells (DCs) pulsed either with ovalbumin-derived CTL or T helper epitopes. These immunizations protected animals from s.c. challenge with ovalbumin-expressing M05 melanoma (class I+ and class II-negative). Notably, antiovalbumin CTL responses were observed in animals vaccinated with an ovalbumin-derived T helper epitope but only after the mice were challenged with M05 cells. This cross-priming of CTL was dependent on both CD4+ and CD8+ T cells. Because we observed that s.c., but not intracranial, tumors were infiltrated with CD11c+ DCs, and because IFN-alpha promotes the activation and survival of both DCs and T cells, we evaluated the combinational antitumor effects of injecting adenoviral (Ad)-IFN-alpha-engineered DCs into intracranial M05 tumors in preimmunized mice. Delivery of DC-IFN-alpha prolonged survival. This was most notable for animals prevaccinated with both the CTL and T helper ovalbumin epitopes, with 60% (6 of 10) of mice (versus 0 of 10 of control animals) surviving for > 80 days after tumor challenge. DC-IFN-alpha appeared to persist longer than mock-transfected DCs within the intracranial tumor microenvironment, and DC-IFN-alpha-treated mice exhibited enhanced levels of ovalbumin-specific CTL in draining cervical lymph nodes. On the basis of these results, we believe that local expression of IFN-alpha by DCs within the intracranial tumor site may enhance the clinical efficacy of peripheral vaccine approaches for brain tumors.
Departments of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213, USA. okadah@msx.upmc.edu
Hideho
H
Okada
Takahiko
T
Tsugawa
Hidemitsu
H
Sato
Naruo
N
Kuwashima
Andrea
A
Gambotto
Kaori
K
Okada
Jill E
JE
Dusak
Wendy K
WK
Fellows-Mayle
Glenn D
GD
Papworth
Simon C
SC
Watkins
William H
WH
Chambers
Douglas M
DM
Potter
Walter J
WJ
Storkus
Ian F
IF
Pollack
D000595:Amino Acid Sequence; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D019496:Cancer Vaccines / Q000276:immunology* / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014162:Transfection
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D016898:Interferon-alpha; D010047:Ovalbumin