title: RIG-I helicase-independent pathway in sendai virus-activated dendritic cells is critical for preventing lung metastasis of AT6.3 prostate cancer.
abstract: We recently demonstrated highly efficient antitumor immunity against dermal tumors of B16F10 murine melanoma with the use of dendritic cells (DCs) activated by replication-competent, as well as nontransmissible-type, recombinant Sendai viruses (rSeV), and proposed a new concept, "immunostimulatory virotherapy," for cancer immunotherapy. However, there has been little information on the efficacies of this method: 1) in more clinically relevant situations including metastatic diseases, 2) on other tumor types and other animal species, and 3) on the related molecular/cellular mechanisms. In this study, therefore, we investigated the efficacy of vaccinating DCs activated by fusion gene-deleted nontransmissible rSeV on a rat model of lung metastasis using a highly malignant subline of Dunning R-3327 prostate cancer, AT6.3. rSeV/dF-green fluorescent protein (GFP)-activated bone marrow-derived DCs (rSeV/dF-GFP-DC), consistent with results previously observed in murine DCs. Vaccination of rSeV/dF-GFP-DC was highly effective at preventing lung metastasis after intravenous loading of R-3327 tumor cells, compared with the effects observed with immature DCs or lipopolysaccharide-activated DCs. Interestingly, neither CTL activity nor DC trafficking showed any apparent difference among groups. Notably, rSeV/dF-DCs expressing a dominant-negative mutant of retinoic acid-inducible gene I (RIG-I) (rSeV/dF-RIGIC-DC), an RNA helicase that recognizes the rSeV genome for inducing type I interferons, largely lost the expression of proinflammatory cytokines without any impairment of antitumor activity. These results indicate the essential role of RIG-I-independent signaling on antimetastatic effect induced by rSeV-activated DCs and may provide important insights to DC-based immunotherapy for advanced malignancies.
authors.affiliation: Department of Gene Therapy, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kato
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Ueda
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kinoh
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yoneyama
authors.forename: Akinao
authors.initials: A
authors.lastname: Matsunaga
authors.forename: Atsushi
authors.initials: A
authors.lastname: Komaru
authors.forename: Yui
authors.initials: Y
authors.lastname: Harada
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Akira
authors.initials: A
authors.lastname: Komiya
authors.forename: Satoko
authors.initials: S
authors.lastname: Shibata
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Hayashi
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ichikawa
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005434:Flow Cytometry; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D016219:Immunotherapy, Adoptive / Q000379:methods; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008175:Lung Neoplasms / Q000276:immunology* / Q000517:prevention & control / Q000556:secondary; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D020365:RNA Helicases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D029082:Sendai virus / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma; C556407:RIG-I protein, rat; D020365:RNA Helicases