title: Targeting the immunoregulator SRA/CD204 potentiates specific dendritic cell vaccine-induced T-cell response and antitumor immunity.
abstract: Although dendritic cell (DC) vaccines offer promise as cancer immunotherapy, further improvements are needed to amplify their clinical therapeutic efficacy. The pattern recognition scavenger receptor SRA/CD204 attenuates the ability of DCs to activate CD8(+) T-cell responses. Therefore, we examined the impact of SRA/CD204 on antitumor responses generated by DC vaccines and we also evaluated the feasibility of enhancing DC vaccine potency by SRA/CD204 blockade. DCs from SRA/CD204-deficient mice were more immunogenic in generating antitumor responses to B16 melanoma, compared with DCs from wild-type mice. Similarly, siRNA-mediated knockdown of SRA/CD204 by lentiviral vectors improved the ability of wild-type DCs to stimulate the expansion and activation of CD8(+) T cells specific for idealized or established melanoma antigens in mice. Using SRA/CD204-silenced DCs to generate antigen-targeted vaccines, we documented a marked increase in the level of antitumor immunity achieved against established B16 tumors and metastases. This increase was associated with enhanced activation of antigen specific CTLs, greater tumor infiltration by CD8(+) T cells and NK cells, and increased intratumoral ratios of both CD4(+) and CD8(+) T-effector cells to CD4(+)CD25(+) T-regulatory cells. Our studies establish that downregulating SRA/CD204 strongly enhances DC-mediated antitumor immunity. In addition, they provide a rationale to enhance DC vaccine potency through SRA/CD204-targeting approaches that can improve clinical outcomes in cancer treatment.
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
authors.forename: Huanfa
authors.initials: H
authors.lastname: Yi
authors.forename: Chunqing
authors.initials: C
authors.lastname: Guo
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yu
authors.forename: Ping
authors.initials: P
authors.lastname: Gao
authors.forename: Jie
authors.initials: J
authors.lastname: Qian
authors.forename: Daming
authors.initials: D
authors.lastname: Zuo
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: John R
authors.initials: JR
authors.lastname: Subjeck
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Wang
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology*; D004354:Drug Screening Assays, Antitumor; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000494:pharmacology / Q000627:therapeutic use*; D016233:Immunotherapy, Active; D016219:Immunotherapy, Adoptive; D016086:Lentivirus / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use*; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation; D014611:Vaccination
chemical_list: D019496:Cancer Vaccines; C495140:Msr1 protein, mouse; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A