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Blockade of Ctla-4 Increases Anti-Tumor Response Inducing Potential of Dendritic Cell Vaccine Publisher Pubmed



Esmaily M1 ; Masjedi A2, 3 ; Hallaj S3 ; Nabi Afjadi M4 ; Malakotikhah F5 ; Ghani S6 ; Ahmadi A7 ; Sojoodi M8 ; Hassannia H9 ; Atyabi F10 ; Namdar A11 ; Azizi G12 ; Ghalamfarsa G13 ; Jadidiniaragh F14, 15
Authors
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Authors Affiliations
  1. 1. Department of Medical Entomology and Vector Control, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
  3. 3. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  4. 4. Department of Biochemistry, Faculty of Biological Science, University of Tarbiat Modares, Tehran, Iran
  5. 5. Department of Clinical Biochemistry, Islamic Azad University, Falavarjan Branch, Isfahan, Iran
  6. 6. Student Research Committee, Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  7. 7. Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, 35899, AL, United States
  8. 8. Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, United States
  9. 9. Immunogenetic Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
  10. 10. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
  11. 11. Department of Oncology, Cross Cancer Institute, The University of Alberta, Edmonton, AB, Canada
  12. 12. Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
  13. 13. Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
  14. 14. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
  15. 15. Department of Immunology, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Source: Journal of Controlled Release Published:2020


Abstract

The immunosuppressive state of the tumor microenvironment diminishes the efficacy of dendritic cell (DC)-based cancer immunotherapy. Inhibitory immune checkpoint molecules expressed on tumor-infiltrating T lymphocytes, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) molecules are one of the main barriers in priming T cells by DCs. Therefore, it seems that blockade of such molecules facilitates the T cells activation by the DC vaccine. In this study, we intended to suppress the expression of CTLA-4 molecule on tumor-infiltrating T cells by siRNA-loaded chitosan-lactate (CL) nanoparticles to facilitate priming anti- tumor T cells by tumor lysate-loaded DC vaccine. Nanoparticles (NPs) have also provided an opportunity for specific drug delivery into the tumor site. CL NPs exhibited favorable physicochemical characteristics (size about 75 nm, polydispersive index<0.2, and a zeta potential about 14), which were associated with a high transfection rate and low toxicity. Moreover, the administration of anti-CTLA-4 siRNA-loaded NPs into CT26 and 4 T1 tumor -bearing mice led to the downregulation of CTLA-4 on tumor -infiltrating T cells, which was associated with tumor regression and increased mice survival. Moreover, while the treatment of tumor -bearing mice with DC vaccine had mild therapeutic outcomes, its combination with siRNA-loaded NPs may exhibit synergistic anti- tumor effects. This possible synergistic ameliorating effect is achieved through the reduction of immunosuppressive cells, the improved cytotoxicity of T lymphocytes, decreased inhibitory and increased inflammatory cytokines, and reduced angiogenesis and metastasis processes. These results indicate that the silencing of CTLA-4 can potentiate the T cell priming capacity of the DC vaccine, proposing a practical anti-cancer therapeutic approach. © 2020 Elsevier B.V.
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