Asal Barshidi1, Vahid Karpisheh2, Fatemeh Karimian Noukabadi3, Fariba Karoon Kiani1, Mohammad Mohammadi4, Negin Afsharimanesh5, Farbod Ebrahimi6, Seyed Hossein Kiaie7,8, Jamshid Gholizadeh Navashenaq9, Mohammad Hojjat-Farsangi10,11, Naime Majidi Zolbanin12,13, Ata Mahmoodpoor14, Hadi Hassannia15, Sanam Nami1, Pooya Jalali1, Reza Jafari16, Farhad Jadidi-Niaragh17,18,19. 1. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 2. Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. 3. Department of Biotechnology, Falavarjan Branch, Islamic Azad University, Isfahan, Iran. 4. Department of Cell and Molecular Biology, School of Advanced Sciences, Islamic Azad University, Tehran Medical Branch, Tehran, , Iran. 5. Department of Microbiology, Faculty of Basic Sciences, Hamedan Branch, Islamic Azad University, Hamedan, Iran. 6. Nanoparticle Process Technology, Faculty of Engineering, University of Duisburg-Essen, Duisburg, Germany. 7. Department of Pharmaceutics, Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. 8. Nano Drug Delivery Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran. 9. Noncommunicable Diseases Research Center, Bam University of Medical Sciences, Bam, Iran. 10. Bioclinicum, Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. 11. The Persian Gulf Marine Biotechnology Medicine Research Center, Bushehr University of Medical Sciences, Bushehr, Iran. 12. Experimental and Applied Pharmaceutical Sciences Research Center,, Urmia University of Medical Sciences, Urmia, Iran. 13. Department of Pharmacology and Toxicology, School of Pharmacy, , Urmia University of Medical Sciences, Urmia, Iran. 14. Department of Anesthesiology, School of Medicine, Imam Reza Medical Research & Training Hospital, Tabriz University of Medical Sciences, Tabriz, Iran. 15. Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran. 16. Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran. jafari.reza@umsu.ac.ir. 17. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. jadidif@tbzmed.ac.ir. 18. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. jadidif@tbzmed.ac.ir. 19. Research Center for Integrative Medicine in Aging, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran. jadidif@tbzmed.ac.ir.
Abstract
PURPOSE: Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS: We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS: Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION: These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.
PURPOSE: Increasing the efficiency of unsuccessful immunotherapy methods is one of the most important research fields. Therefore, the use of combination therapy is considered as one of the ways to increase the effectiveness of the dendritic cell (DC) vaccine. In this study, the inhibition of immune checkpoint receptors such as LAG3 and PD-1 on T cells was investigated to increase the efficiency of T cells in response to the DC vaccine. METHODS: We used trimethyl chitosan-dextran sulfate-lactate (TMC-DS-L) nanoparticles (NPs) loaded with siRNA molecules to quench the PD-1 and LAG3 checkpoints' expression. RESULTS: Appropriate physicochemical characteristics of the generated NPs led to efficient inhibition of LAG3 and PD-1 on T cells, which was associated with increased survival and activity of T cells, ex vivo. Also, treating mice with established breast tumors (4T1) using NPs loaded with siRNA molecules in combination with DC vaccine pulsed with tumor lysate significantly inhibited tumor growth and increased survival in mice. These ameliorative effects were associated with increased anti-tumor T cell responses and downregulation of immunosuppressive cells in the tumor microenvironment and spleen. CONCLUSION: These findings strongly suggest that TMC-DS-L NPs loaded with siRNA could act as a novel tool in inhibiting the expression of immune checkpoints in the tumor microenvironment. Also, combination therapy based on inhibition of PD-1 and LAG3 in combination with DC vaccine is an effective method in treating cancer that needs to be further studied.
Authors: S A Rosenberg; J C Yang; D J Schwartzentruber; P Hwu; F M Marincola; S L Topalian; N P Restifo; M E Dudley; S L Schwarz; P J Spiess; J R Wunderlich; M R Parkhurst; Y Kawakami; C A Seipp; J H Einhorn; D E White Journal: Nat Med Date: 1998-03 Impact factor: 53.440
Authors: Mehrdad Fathi; Inna Pustokhina; Sergey V Kuznetsov; Mars Khayrullin; Mohammad Hojjat-Farsangi; Vahid Karpisheh; Ali Jalili; Farhad Jadidi-Niaragh Journal: IUBMB Life Date: 2021-03-30 Impact factor: 3.885