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

Abstract

Introduction: Immune checkpoint therapy is well- established therapeutic approach in treatment of malignant disease and is thought to be mostly based on facilitating adaptive immune responses. However, cells of innate immune response, such as NKT cells, might also be important for successful anti-programmed cell death protein 1 therapy, as they initiate anti-tumor immune response. Materials and methods: For tumor induction, 4T1 cells syngenic to BALB/c background were used after which mice underwent anti-programmed cell death protein 1 treatment.After the mice were sacrificed, NKT cells, dendritic cells and macrophages derived from spleen and primary tumor tissue were analyzed using flow cytometry. Results: Anti-programmed cell death protein 1 therapy significantly decelerates tumor growth and enhanced expression of activating molecules CD69, NKp46, NKG2D in NKT cells of tumor and spleen. Anti-programmed cell death protein 1 therapy activates pro-tumoricidic changes in dendritic cells and macrophages of primary tumor tissue. Conclusion: Anti-programmed cell death protein 1 therapy activates NKT cell directly, and indirectly via DCs. Activated NKT cells provide tumoricidic properties directly, by secreting perforin, and indirectly by stimulating M1 macrophages polarization. Since anti-programmed cell death protein 1 therapy induces significant changes in NKT cells, dendritic cells and macrophages, efficacy of overall anti-programmed cell death protein 1 therapy is increased, contributing to more efficient anti-tumor immune response.

Innate immunity and early liver inflammation

“…α-PD-1 therapy has shown to invigorate bacteria clearance, but it also suggests that KCs may have impaired tolerogenic function to self-antigens reactive T cells. NKT cells also responded to α-PD-1 therapy and exert increased anti-tumor functions by secretion of IFN- γ secretion of inflammatory cytokines ( 205 ).…”

Metformin as a Potential Antitumor Agent

“…One of the ways in which metformin influences immune responses to cancer is by modulating the expression of the programmed death ligand (PD-L1, also known as CD274 or B7-H1) (60). Studies have shown that molecule PD-L1 is expressed at significantly higher levels in various cancer types in which it promotes cell proliferation, migration and invasion while the other studies showed that PD-1 can have immunomodulatory effect (61)(62)(63)(64). Role of PD-L1 is to provide an inhibitory signal to cytotoxic T lymphocytes (CTLs) through binding to an inhibitory PD-1 receptors on activated CTLs.…”