title: Enhancement of cancer vaccine therapy by systemic delivery of a tumor-targeting Salmonella-based STAT3 shRNA suppresses the growth of established melanoma tumors.
abstract: Cancer vaccine therapies have only achieved limited success when focusing on effector immunity with the goal of eliciting robust tumor-specific T-cell responses. More recently, there is an emerging understanding that effective immunity can only be achieved by coordinate disruption of tumor-derived immunosuppression. Toward that goal, we have developed a potent Salmonella-based vaccine expressing codon-optimized survivin (CO-SVN), referred to as 3342Max. When used alone as a therapeutic vaccine, 3342Max can attenuate growth of aggressive murine melanomas overexpressing SVN. However, under more immunosuppressive conditions, such as those associated with larger tumor volumes, we found that the vaccine was ineffective. Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a short hairpin RNA (shRNA) targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4(+) and CD8(+) T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets. Interestingly, mice treated with YS1646-shSTAT3 or 3342Max alone were similarly unsuccessful in rejecting established tumors, whereas the combined regimen was highly potent. Our findings establish that a combined strategy of silencing immunosuppressive molecules followed by vaccination can act synergistically to attenuate tumor growth, and they offer a novel translational direction to improve tumor immunotherapy.
authors.affiliation: Division of Translational Vaccine Research, City of Hope, Duarte, California 91010, USA.
authors.forename: Edwin R
authors.initials: ER
authors.lastname: Manuel
authors.forename: Céline A
authors.initials: CA
authors.lastname: Blache
authors.forename: Rebecca
authors.initials: R
authors.lastname: Paquette
authors.forename: Teodora I
authors.initials: TI
authors.lastname: Kaltcheva
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Ishizaki
authors.forename: Joshua D I
authors.initials: JD
authors.lastname: Ellenhorn
authors.forename: Michael
authors.initials: M
authors.lastname: Hensel
authors.forename: Leonid
authors.initials: L
authors.lastname: Metelitsa
authors.forename: Don J
authors.initials: DJ
authors.lastname: Diamond
mesh_terms: D000818:Animals; D017209:Apoptosis; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003062:Codon; D003602:Cytotoxicity, Immunologic; D005822:Genetic Vectors; D016233:Immunotherapy, Active; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008546:Melanoma, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D000077022:Survivin; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: C117749:Birc5 protein, mouse; D019496:Cancer Vaccines; D003062:Codon; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000077022:Survivin