Synergistic effect of programmed cell death protein 1 blockade and secondary lymphoid tissue chemokine in the induction of anti-tumor immunity by a therapeutic cancer vaccine

• Published in: Archives of virology 2017-02, Vol.162 (2), p.333-346
• Main Authors: Moeini, Soheila, Saeidi, Mohsen, Fotouhi, Fatemeh, Mondanizadeh, Mahdieh, Shirian, Sadegh, Mohebi, Alireza, Gorji, Ali, Ghaemi, Amir
• Format: Article
• Language: English
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Antibodies, Neutralizing - pharmacology; Antigens; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Biomedical and Life Sciences; Biomedicine; Cancer vaccines; Cancer Vaccines - administration & dosage; Cancer Vaccines - genetics; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell death; Cervical cancer; Chemokine CCL21 - pharmacology; Chemokines; Cytokines; Cytotoxicity; Dendritic cells; Disease Models, Animal; Female; Gene Expression Regulation, Neoplastic - immunology; Human papillomavirus; Human papillomavirus 16 - drug effects; Human papillomavirus 16 - genetics; Human papillomavirus 16 - immunology; Humans; Immunotherapy; Infectious Diseases; Interferon-gamma - genetics; Interferon-gamma - immunology; Interleukin-10 - genetics; Interleukin-10 - immunology; Interleukin-4 - genetics; Interleukin-4 - immunology; Lymphocytes; Medical Microbiology; Mice; Original Article; Papillomavirus E7 Proteins - genetics; Papillomavirus E7 Proteins - immunology; Papillomavirus Infections - immunology; Papillomavirus Infections - prevention & control; Papillomavirus Infections - virology; Plasmids - chemistry; Plasmids - immunology; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Proteins; Research centers; Signal Transduction; Spleen - drug effects; Spleen - immunology; Spleen - pathology; Tumors; Uterine Cervical Neoplasms - immunology; Uterine Cervical Neoplasms - prevention & control; Uterine Cervical Neoplasms - virology; Vaccines, DNA - administration & dosage; Vaccines, DNA - genetics; Vaccines, DNA - immunology; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - immunology; Virology
• ISSN: 0304-8608; 1432-8798
• DOI: 10.1007/s00705-016-3091-5

The use of DNA vaccines has become an attractive approach for generating antigen-specific cytotoxic CD8 + T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be improved by using an adjuvant injected together with checkpoint antibodies. In the current study, we evaluated whether the therapeutic effects of a DNA vaccine encoding human papilloma virus type 16 (HPV-16) E7 can be enhanced by combined application of an immune checkpoint blockade directed against the programmed death-1 (PD-1) pathway and secondary lymphoid tissue chemokine (SLC) also known as CCL21 adjuvant, in a mouse cervical cancer model. The therapeutic effects of the DNA vaccine in combination with CCL21 adjuvant plus PD-1 blockade was evaluated using a tumor growth curve. To further investigate the mechanism underlying the antitumor response, cytolytic and lymphocyte proliferation responses in splenocytes were measured using non-radioactive cytotoxicity and MTT assays, respectively. Vascular endothelial growth factor (VEGF) and IL-10 expression in the tumor and the levels of IFN-γ and IL-4 in supernatants of spleno-lymphocyte cultures were measured using ELISA. The immune efficacy was evaluated by in vivo  tumor regression assay. The results showed that vaccination with a DNA vaccine in combination with the CCL21 adjuvant plus PD-1 blockade greatly enhanced cytotoxic T lymphocyte production and lymphocyte proliferation rates and greatly inhibited tumor progression. Moreover, the vaccine in combination with adjuvant and blockade significantly reduced intratumoral VEGF, IL-10 and splenic IL-4 but induced the expression of splenic IFN-γ. This formulation could be an effective candidate for a vaccine against cervical cancers and merits further investigation.