Abrine Elicits Liver Carcinoma Immunity and Enhances Antitumor Efficacy of Immune Checkpoint Blockade by Modulating PD-L1 Signaling.

Abstract

Background Liver cancer is the most malignant type of human malignancies. In recent years, immune therapy that targets the immune check points such as programmed cell death ligand 1 (PD-L1) has achieve great success. Abrine is the dominant alkaloid in Abrus cantoniensis and Abrus precatorius Linn. that exhibited anticancer effect. This work is aimed at studying the effects of abrine in immunity of liver cancer. Methods Cell viability, proliferation, and migration were assessed by CCK-8, Edu, and Transwell assay. Cell apoptosis was checked by flow cytometry. Tumor growth was determined by an in vivo xenograft model. Quantitative real-time PCR assay was conducted to evaluate the levels of KAT5 and PD-L1. T cells and liver cancer cells were cocultured in a Transwell system, and the levels of PD-L1 and PD-1 was checked by flow cytometry. The interaction between KAT5 and PD-L1 was determined by ChIP assay. Results Abrine treatment suppressed liver tumor growth both in vitro and in vivo and simultaneously decreased the level of PD-L1 and KAT5. In the coculture system, treatment with abrine inhibited proliferation and activity of cocultured T cell. KAT5 epigenetically elevated recruitment of H3k27ac and RNA polymerase II to PD-L1 promoter region. Ectopic expression of KAT5 and PD-L1 reversed the function of abrine on tumor growth and T cell function. Conclusion Abrine modulated growth and apoptosis of liver cancer cells and regulated proliferation and activation of T cells through the KAT5/PD-L1 axis.