Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model

Barshidi, Asal and Karpisheh, Vahid and Karimian Noukabadi, Fatemeh and Mohammadi, Mohammad and Karoon Kiani, Fariba and Afsharimanesh, Negin and Ebrahimi, Farbod and Kiaie, Seyed Hossein and Gholizadeh Navashenaq, Jamshid and Hojjat-Farsangi, Mohammad and Majidi Zolbanin, Naime and Mahmoodpoor, Ata and Hassannia, Hadi and Nami, Sanam and Jalali, Pooya and Jafari, Reza and Jadidi-Niaragh, Farhad (2022) Dual Blockade of PD-1 and LAG3 Immune Checkpoints Increases Dendritic Cell Vaccine Mediated T Cell Responses in Breast Cancer Model. Pharmaceutical Research. ISSN 0724-8741

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Official URL: https://link.springer.com/article/10.1007/s11095-0...


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.

Item Type: Article
Subjects: QW Microbiology and Immunology
Divisions: Faculty of Medicin > Department of Immunology and Allergy
Depositing User: خدیجه شبانکاره
Date Deposited: 10 Oct 2022 10:45
Last Modified: 10 Oct 2022 10:45
URI: http://eprints.bpums.ac.ir/id/eprint/9571

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