Interleukin 18 gene transfer expands the repertoire of antitumor Th1-type immunity elicited by dendritic cell-based vaccines in association with enhanced therapeutic efficacy.
Dendritic cells (DCs) are potent antigen-presenting cells that can prime and boost systemic antitumor immunity. Here, we have evaluated the ability of DCs transfected to secrete the potent Th1-biasing cytokine interleukin (IL)-18 to promote enhanced antitumor immunity in a mouse sarcoma model. DCs infected with a recombinant adenovirus encoding IL-18 (AdIL18DC) expressed higher levels of MHC and costimulatory molecules and were better stimulators than control DCs in mixed leukocyte reactions in vitro. Immunization of BALB/c mice bearing established day 7 CMS4 tumors with tumor peptide-pulsed control Adpsi5-transfected DCs or nontransduced DCs significantly inhibited the growth of established tumors but did not lead to complete regression of established tumors. Importantly, immunization with antigen-loaded AdIL18DC resulted in tumor rejection or further suppression of tumor growth when compared with controls. The repertoire of naturally presented tumor peptides recognized by splenocytes (as deduced in IFN-gamma ELISA assays) from AdIL18DC-treated animals was far more diverse and of greater magnitude than that of all other groups, in association with improved therapeutic outcome. These results support the ability of IL-18 gene transfer to enhance the capacity of DCs to drive broadly reactive Th1-type therapeutic immunity prompted by single peptide epitope-based vaccines (i.e., epitope spreading).
Tatsumi
Tomohide
T
Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15261, USA.
Gambotto
Andrea
A
Robbins
Paul D
PD
Storkus
Walter J
WJ
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D005260:Female; D018014:Gene Transfer Techniques; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D012513:Sarcoma, Experimental / Q000276:immunology / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*
D019496:Cancer Vaccines; D020382:Interleukin-18; D007371:Interferon-gamma