Brucea javanica oil emulsion significantly improved the effect of anti-programmed cell death protein-1 immunotherapy.

ABSTRACT

BACKGROUND: Brucea javanica oil (BJO) is the active substance extracted from the dry and mature fruit of Brucea javanica. Its pharmaceutical preparation, BJO emulsion (BJOE), is one of the most widely studied traditional Chinese medicine preparations for the treatment of malignancy. However, the unrevealed anti-tumor mechanism immensely limits further development of BJOE. PURPOSE: In this study, we delved into the anti-tumor mechanism of commercial BJOE, including its influence on the tumor microenvironment (TME) and the treatment effect when combined with anti-programmed cell death protein-1 (PD-1) therapy. METHODS: The cytotoxicity of BJOE was tested in different cells in vitro, and a Förster resonance energy transfer system was also constructed to predict the release behavior of BJOE in vivo. Then, a B16 melanoma mouse model was used to explore the combination of BJOE and anti-mouse PD-1 antibody therapy. In addition, mass cytometry was used to test the impact of both drugs on the TME. RESULTS: Out data revealed that BJOE did not directly kill tumor cells in vitro. However, BJOE was mainly released at the tumor site, converting an immunosuppressive TME into an immune-activated state, and its combination with anti-PD-1 therapy significantly inhibited the growth of melanoma and prolonged the survival time of the mice due to an increase in cytotoxic T lymph (CD8+ T) and helper/inducible T lymph (CD4+ T) cells in lymph nodes and tumors. CONCLUSIONS: Our work explored the anti-tumor mechanism of commercial BJOE and the regulation of cytokines by BJOE when it was combined with anti-PD-1 therapy in vivo. The combination of these therapies could increase the numbers of CD4+ T-cells, CD8+ T-cells, and effective natural killer cells and the ratio of MI/M2 macrophages in tumor tissues, promoting inflammatory activity and enhancing the anti-tumor effect. This study provides a theoretical basis for advancing the modern development of traditional Chinese medicine preparations and stands as a reference for clinically improving the efficacy of PD-1 antibodies.