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- W2977401980 abstract "Abstract Background Romidepsin (FK228), a histone deacetylase inhibitor (HDACi), has anti-tumor effects against several types of solid tumors. Studies have suggested that HDACi could upregulate PD-L1 expression in tumor cells, changing the state of anti-tumor immune responses. However, the influence of enhanced PD-L1 expression in tumor cells induced by romidepsin on anti-tumor immune responses are still under debate. So, the purpose of this study was to explore the anti-tumor effects and influence on immune responses of romidepsin in colon cancer. Methods The effects of romidepsin on proliferation, cell cycle and apoptosis in the murine colon cancer cell lines CT26 and MC38 were evaluated. PD-L1 expression levels were examined before and after treatment with romidepsin. To analyze the mechanisms through which romidepsin regulates PD-L1 expression, the acetylation of histones H3 and H4 and transcription factor BRD4 was measured. The influence of romidepsin on FOXP3+ regulatory T cells (Tregs), Th1/Th2 balance and IFN-γ+CD8+ T cells was evaluated in a subcutaneous transplanted tumor model and a colitis-associated cancer (CAC) model. Results The results indicated that romidepsin inhibited proliferation, induced G0/G1 cell cycle arrest and increased apoptosis in CT26 and MC38 cells. Romidepsin treatment increased PD-L1 expression in CT26 and MC38 cells via increasing the acetylation levels of histones H3 and H4 and regulating the transcription factor BRD4. In subcutaneous transplant tumor mice and CAC mice, romidepsin increased the percentage of FOXP3+ Tregs, decreased the ratio of Th1/Th2 cells and decreased the percentage of IFN-γ+CD8+ T cells in the peripheral blood and the tumor microenvironment. Upon combination with an anti-PD-1 antibody, the anti-tumor effects were enhanced, and the influence on CD4+ and CD8+ T cells was partially reversed. Conclusions Although romidepsin had direct anti-tumor effects in murine colon cancer, it increased PD-L1 expression in tumor cells and the percentage of immune-suppressive cells. Combination with anti-PD-1 antibody augmented the anti-tumor effects by reversing the influence of romidepsin on immune cells. Legal entity responsible for the study The author. Funding National Natural Science Foundation of China. Disclosure The author has declared no conflicts of interest." @default.
- W2977401980 created "2019-10-10" @default.
- W2977401980 creator A5068659124 @default.
- W2977401980 date "2019-10-01" @default.
- W2977401980 modified "2023-10-16" @default.
- W2977401980 title "Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and exerts synergistic anti-tumour activity with an anti-PD-1 antibody in colon cancer" @default.
- W2977401980 doi "https://doi.org/10.1093/annonc/mdz246.086" @default.
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