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.
Okada
Hideho
H
Departments of Neurological Surgery, University of Pittsburgh School of Medicine, PA 15213, USA. okadah@msx.upmc.edu
Tsugawa
Takahiko
T
Sato
Hidemitsu
H
Kuwashima
Naruo
N
Gambotto
Andrea
A
Okada
Kaori
K
Dusak
Jill E
JE
Fellows-Mayle
Wendy K
WK
Papworth
Glenn D
GD
Watkins
Simon C
SC
Chambers
William H
WH
Potter
Douglas M
DM
Storkus
Walter J
WJ
Pollack
Ian F
IF
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