Enhanced therapeutic efficacy of tumor RNA-pulsed dendritic cells after genetic modification with lymphotactin.
Pulsing dendritic cells (DCs) with tumor cell-derived mRNA is regarded as an attractive alternative in the development of DC-based tumor vaccines. Our aim is to improve the therapeutic efficacy of DC-based tumor RNA vaccines by augmenting the preferential chemotaxis of DCs to T cells. Mouse bone marrow-derived DCs were genetically modified with lymphotactin (Lptn) by adenovirus vector, which conferred on DCs preferential chemotaxis to CD4+ and CD8+ T cells (Cao et al., 1998). Lptn gene-modified DCs (Lptn-DCs) were pulsed with tumor mRNA and used for vaccination in the tumor models of 3LL lung carcinoma and B16 melanoma. In both tumor models, immunization with 4 X 10(4) tumor RNA-pulsed Lptn-DCs induced more potent CTL activity, compared with their counterparts, specifically against tumor cells and Mut1 or tyrosinase-related protein 2 (TRP-2) peptide-pulsed RMA-S cells, and rendered the immunized mice resistant to tumor challenge much more effectively. CD8+ T cells were necessary and sufficient to generate the protection of Lptn-DC-based RNA tumor vaccines, and CD4+ T cells were required for the induction of tumor rejection. In the preestablished 3LL and B16 tumor models, vaccination with DC-based or LacZ-DC-based tumor RNA vaccines (2 X 10(5) cells) could reduce pulmonary metastasis and extend survival of tumor-bearing mice, but was less effective than the Lptn-DC counterpart (with 60-80% mice surviving). When the immunizing dose was decreased to 4 X 10(4) cells, Lptn-DC-based tumor vaccines rather than their counterparts were still significantly effective. Our studies provide a potential strategy to improve the efficacy of DC-based vaccines, and a new approach to immunological intervention by chemokines.
Zhang
W
W
Department of Immunology, Second Military Medical University, Shanghai, People's Republic of China.
He
L
L
Yuan
Z
Z
Xie
Z
Z
Wang
J
J
Hamada
H
H
Cao
X
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D019744:Chemokines, C; D003713:Dendritic Cells / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008222:Lymphokines / Q000235:genetics*; D008546:Melanoma, Experimental / Q000556:secondary / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics*; D012795:Sialoglycoproteins / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D019496:Cancer Vaccines; D019744:Chemokines, C; D008222:Lymphokines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012795:Sialoglycoproteins; C092390:XCL1 protein, human; C486249:Xcl1 protein, mouse; C018997:lymphotactin