TY - JOUR
T1 - RIG-I helicase-independent pathway in Sendai virus-activated dendritic cells is critical for preventing lung metastasis of AT6.3 prostate cancer
AU - Kato, Tomonori
AU - Ueda, Yasuji
AU - Kinoh, Hiroaki
AU - Yoneyama, Yasuo
AU - Matsunaga, Akinao
AU - Komaru, Atsushi
AU - Harada, Yui
AU - Suzuki, Hiroyoshi
AU - Komiya, Akira
AU - Shibata, Satoko
AU - Hasegawa, Mamoru
AU - Hayashi, Hideki
AU - Ichikawa, Tomohiko
AU - Yonemitsu, Yoshikazu
N1 - Funding Information:
Abbreviations: BM-DC, bone marrow–derived DC; DC, dendritic cells; GFP, green fluorescent protein; i.v., intravenous injection; iDC, immature DC; LPS, lipopolysaccharide; LPS-DC, LPS-activated DC; MOI, multiplicity of infection; RIG-I, retinoic acid–inducible gene I; rSeV, recombinant Sendai virus; rSeV/dF, fusion gene–deleted rSeV; rSeV/ dF-RIGIC, rSeV/dF expressing dominant-negative mutant of RIG-I; s.c., subcutaneous injection Address all correspondence to: Yoshikazu Yonemitsu, MD, PhD, R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Rm. 505 Collaborative Research Station II, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: yonemitu@med.kyushu-u.ac.jp 1This work was supported in part by research grants from the 21st Century Center of Excellence Program, Chiba University Graduate School of Medicine; by grants-in-aid (to T.I. and Y.Y.) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology; by research grants from Sankyo Foundation of Life Science (to Y.Y.), Mitsubishi Pharma Research Foundation (to Y.Y.), and Uehara Memorial Foundation (to Y.Y.). 2Dr. Yonemitsu is a member of the Scientific Advisory Board of DNAVEC Corporation. 3This article refers to supplementary materials, which are designated by Table W1 and Figure W1 and are available online at www.neoplasia.com. Received 25 May 2010; Revised 2 August 2010; Accepted 3 August 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1522-8002/10/$25.00 DOI 10.1593/neo.10732
PY - 2010/11
Y1 - 2010/11
N2 - 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 thismethod: 1) inmore 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 dominantnegative 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.
AB - 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 thismethod: 1) inmore 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 dominantnegative 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.
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U2 - 10.1593/neo.10732
DO - 10.1593/neo.10732
M3 - Article
C2 - 21076616
AN - SCOPUS:78449258707
VL - 12
SP - 906
EP - 914
JO - Neoplasia
JF - Neoplasia
SN - 1522-8002
IS - 11
ER -