Anti-PD-1 therapy activates tumoricidic properties of NKT cells and contributes to the overall deceleration of tumor progression in a model of murine mammary carcinoma

Marina Jovanović; Nevena  Gajović; Milena  Jurišević; Sofija Sekulić; Nebojša Arsenijević; Miodrag Jocić; Milan Jovanović; Ružica Lukić; Ivana Jovanović; Dragče Radovanović

doi:10.2298/VSP210126039J

Marina Jovanović University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia
Nevena Gajović University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia
Milena Jurišević University of Kragujevac, Faculty of Medical Sciences, Department of Pharmacy, Kragujevac, Serbia
Sofija Sekulić University of Kragujevac, Faculty of Medical Sciences, Department of Infectious Diseases, Kragujevac, Serbia
Nebojša Arsenijević University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia
Miodrag Jocić Military Medical Academy, §Institute for Transfusiology and Haemobiology, Belgrade, Serbia
Milan Jovanović Military Medical Academy, Clinic for Abdominal Surgery, Belgrade, Serbia
Ružica Lukić University of East Sarajevo, Faculty of Medicine, Department of Microbiology, Foča, Bosnia and Herzegovina
Ivana Jovanović University of Kragujevac, Faculty of Medical Sciences, Center for Molecular Medicine and Stem Cell Research, Kragujevac, Serbia
Dragče Radovanović University of Kragujevac, Faculty of Medical Sciences, Department of Surgery, Kragujevac, Serbia

DOI: https://doi.org/10.2298/VSP210126039J

Keywords: antineoplastic agents;, breast neoplasms;, immunomodulation;, killer cell, natural;, macrophages;, mice.

Abstract

Background/Aim. Immune checkpoint therapy is a well-established therapeutic approach in the treatment of malignant diseases and is thought to be mostly based on facilitating the adaptive immune response. However, the cells of the innate immune response, such as natural killer T (NKT) cells, might also be important for a successful anti-programmed cell death protein-1 (anti-PD-1) therapy, as they initiate the antitumor immune response. The aim of this study was to investigate the influence of anti-PD-1 therapy on the immune response against tumors. Methods. For tumor induction, 4T1 cells synergic to BALB/c background were used, after which mice underwent anti-PD-1 treatment. After the mice were sacrificed, NKT cells, dendritic cells (DCs), and macrophages derived from spleen and primary tumor tissue were analyzed using flow cytometry. Results. Anti-PD-1 therapy enhanced the expression of activating molecules CD69, NKp46, and NKG2D in NKT cells of the tumor and spleen. This therapy activated NKT cells directly and indirectly via DCs. Activated NKT cells acquired tumoricidic properties directly, by secreting perforin, and indirectly by stimulating M1 macrophages polarization. Conclusion. Anti-PD-1 therapy activates changes in DCs and macrophages of primary tumor tissue towards protumoricidic activity. Since anti-PD-1 therapy induces significant changes in NKT cells, DCs, and macrophages, the efficacy of the overall antitumor response is increased and has significantly decelerated tumor growth.

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