title: Prime-boost vaccination with SA-4-1BBL costimulatory molecule and survivin eradicates lung carcinoma in CD8+ T and NK cell dependent manner.
abstract: Subunit vaccines containing universal tumor associated antigens (TAAs) present an attractive treatment modality for cancer primarily due to their safety and potential to generate long-term immunological responses that can safeguard against recurrences. However, TAA-based subunit vaccines require potent adjuvants for therapeutic efficacy. Using a novel form of the 4-1BBL costimulatory molecule, SA-4-1BBL, as the adjuvant of choice, we previously demonstrated that a single vaccination with survivin (SVN) as a bona fide self TAA was effective in eradicating weakly immunogenic 3LL tumors in >70% of C57BL/6 mice. The present study was designed to i) assess the therapeutic efficacy of a prime-boost vaccination and ii) investigate the mechanistic basis of vaccine efficacy. Our data shows that a prime-boost vaccination strategy was effective in eradicating 3LL lung carcinoma in 100% of mice. The vaccine efficacy was correlated with increased percentages of CD8(+) T cells expressing IFN-γ as well as potent killing responses of both CD8(+) T and NK cells in the absence of detectable antibodies to ssDNA as a sign of autoimmunity. Antibody depletion of CD8(+) T cells one day before vaccination completely abrogated therapeutic efficacy, whereas depletion of CD4(+) T cells had no effect. Importantly, NK cell depletion had a moderate (∼50% reduction), but significant (p<0.05) effect on vaccine efficacy. Taken together, these results shed light on the mechanistic basis of the SA-4-1BBL/SVN subunit vaccine formulation in a lung carcinoma model and demonstrate the robust therapeutic efficacy of the prime-boost immunization strategy with important clinical implications.
authors.affiliation: Institute for Cellular Therapeutics, Department of Microbiology and Immunology and James Brown Cancer Center, University of Louisville, Louisville, KY, USA.
authors.forename: Abhishek K
authors.initials: AK
authors.lastname: Srivastava
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Sharma
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.forename: Vahap
authors.initials: V
authors.lastname: Ulker
authors.forename: Kathryn
authors.initials: K
authors.lastname: MacLeod
authors.forename: Gunes
authors.initials: G
authors.lastname: Dinc
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D004273:DNA, Neoplasm / Q000276:immunology; D007117:Immunization, Secondary; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D012097:Repressor Proteins / Q000276:immunology*; D000077022:Survivin; D016896:Treatment Outcome; D014611:Vaccination
chemical_list: D053330:4-1BB Ligand; D001323:Autoantibodies; C117749:Birc5 protein, mouse; D019496:Cancer Vaccines; D004273:DNA, Neoplasm; D051034:Inhibitor of Apoptosis Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D000077022:Survivin