Prime-boost vaccination with SA-4-1BBL costimulatory molecule and survivin eradicates lung carcinoma in CD8+ T and NK cell dependent manner

• Published in: PloS one 2012-11, Vol.7 (11), p.e48463-e48463
• Main Authors: Srivastava, Abhishek K, Sharma, Rajesh K, Yolcu, Esma S, Ulker, Vahap, MacLeod, Kathryn, Dinc, Gunes, Shirwan, Haval
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand - immunology; Adjuvants; Animals; Antibodies; Antigen (tumor-associated); Antigens; Autoantibodies - immunology; Autoimmunity; Biology; Cancer; Cancer Vaccines - immunology; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Depletion; DNA, Neoplasm - immunology; Effectiveness; Immunization; Immunization, Secondary; Immunogenicity; Immunology; Inhibitor of Apoptosis Proteins - immunology; Interferon; Killer Cells, Natural - immunology; Lung cancer; Lung carcinoma; Lung Neoplasms - immunology; Lung Neoplasms - prevention & control; Lymphocytes; Lymphocytes T; Medicine; Metastasis; Mice; Mice, Inbred C57BL; Natural killer cells; Proteins; Recombinant Proteins - biosynthesis; Recombinant Proteins - immunology; Repressor Proteins - immunology; Survivin; Treatment Outcome; Tumor necrosis factor-TNF; Tumors; Vaccination; Vaccine efficacy; Vaccines; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048463

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