Romidepsin (FK228) regulates the expression of the immune checkpoint ligand PD-L1 and suppresses cellular immune functions in colon cancer
Open Access
- 1 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cancer Immunology, Immunotherapy
- Vol. 70 (1), 61-73
- https://doi.org/10.1007/s00262-020-02653-1
Abstract
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 and change the state of anti-tumor immune responses in vivo. However, the influence of enhanced PD-L1 expression in tumor cells induced by romidepsin on anti-tumor immune responses is 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. 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 vivo and in vitro via increasing the acetylation levels of histones H3 and H4 and regulating the transcription factor BRD4. In subcutaneous transplant tumor mice and colitis-associated cancer (CAC) mice, romidepsin increased the percentage of FOXP3+ regulatory T cells (Tregs), decreased the ratio of Th1/Th2 cells and the percentage of IFN-gamma+ CD8+ T cells in the peripheral blood and the tumor microenvironment. Upon combination with an anti-PD-1 antibody, the anti-tumor effects of romidepsin were enhanced and the influence on CD4+ and CD8+ T cells was partially reversed. Therefore, the combination of romidepsin and anti-PD-1 immunotherapy provides a more potential treatment for colon cancer.Funding Information
- National Natural Science Foundation of China (81772620)
- National Key R&D Program of China (2018ZX09201015)
- Tianjin Science and Technology Major Project of Chronic Diseases Prevention and Control (17ZXMFSY00130)
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