Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner

Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner

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 pot...

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Main Authors: Srivastava, Abhishek K., Sharma, Rajesh K., Yolcu, Esma S., Ulker, Vahap, MacLeod, Kathryn, Dinc, Gunes, Shirwan, Haval
Format: Online
Language:English
Published: Public Library of Science 2012
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493554/
id pubmed-3493554
recordtype oai_dc
spelling pubmed-34935542012-11-09 Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner Srivastava, Abhishek K. Sharma, Rajesh K. Yolcu, Esma S. Ulker, Vahap MacLeod, Kathryn Dinc, Gunes Shirwan, Haval Research Article 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. Public Library of Science 2012-11-08 /pmc/articles/PMC3493554/ /pubmed/23144888 http://dx.doi.org/10.1371/journal.pone.0048463 Text en © 2012 Srivastava et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Srivastava, Abhishek K.
Sharma, Rajesh K.
Yolcu, Esma S.
Ulker, Vahap
MacLeod, Kathryn
Dinc, Gunes
Shirwan, Haval
spellingShingle Srivastava, Abhishek K.
Sharma, Rajesh K.
Yolcu, Esma S.
Ulker, Vahap
MacLeod, Kathryn
Dinc, Gunes
Shirwan, Haval
Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner
author_facet Srivastava, Abhishek K.
Sharma, Rajesh K.
Yolcu, Esma S.
Ulker, Vahap
MacLeod, Kathryn
Dinc, Gunes
Shirwan, Haval
author_sort Srivastava, Abhishek K.
title Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner
title_short Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner
title_full Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner
title_fullStr Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner
title_full_unstemmed Prime-Boost Vaccination with SA-4-1BBL Costimulatory Molecule and Survivin Eradicates Lung Carcinoma in CD8+ T and NK Cell Dependent Manner
title_sort prime-boost vaccination with sa-4-1bbl costimulatory molecule and survivin eradicates lung carcinoma in cd8+ t and nk cell dependent manner
description 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.
publisher Public Library of Science
publishDate 2012
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493554/
_version_ 1611922864250814464

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