title: 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.
abstract: 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.
authors.affiliation: Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Soheila
authors.initials: S
authors.lastname: Moeini
authors.affiliation: Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Saeidi
authors.affiliation: Department of Virology, Pasteur Institute of Iran, P.O.Box: 1316943551, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Fotouhi
authors.affiliation: Biotechnology and molecular medicine, Arak University of medical sciences, Arak, Iran.
authors.forename: Mahdieh
authors.initials: M
authors.lastname: Mondanizadeh
authors.affiliation: Department of Pathology, School of Veterinary Medicine, Shahrekord University,  Shahrekord, Iran.
authors.forename: Sadegh
authors.initials: S
authors.lastname: Shirian
authors.affiliation: Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran.|Infectious Diseases Research Center, Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Mohebi
authors.affiliation: Institut für Physiologie I, Westfälische Wilhelms-Universität Münster, Robert-Koch-Strasse Münster, Germany.|Shefa Neuroscience Research Center, Tehran, Iran.
authors.forename: Ali
authors.initials: A
authors.lastname: Gorji
authors.affiliation: Department of Virology, Pasteur Institute of Iran, P.O.Box: 1316943551, Tehran, Iran. ghaem_amir@yahoo.com.
authors.forename: Amir
authors.initials: A
authors.lastname: Ghaemi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D054421:Chemokine CCL21 / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D052162:Human papillomavirus 16 / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D051379:Mice; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology*; D030361:Papillomavirus Infections / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D010957:Plasmids / Q000737:chemistry / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D054421:Chemokine CCL21; C556062:IL10 protein, mouse; D050725:Papillomavirus E7 Proteins; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D019444:Vaccines, DNA; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma