HDAC6 inhibitor ACY-1215 enhances STAT1 acetylation to block PD-L1 for colorectal cancer immunotherapy

Abstract

The search for effective combination therapy with immune checkpoint inhibitors (ICI) has become important for cancer patients who do not respond to the ICI well. Histone deacetylases (HDACs) inhibitors have attracted wide attention as anti-tumor agents. ACY-1215 is a selective inhibitor of HDAC6, which can inhibit the growth of a variety of tumor. We previously revealed that HDAC family is highly expressed in colorectal cancer specimens and mouse models. In this study, ACY-1215 was combined with anti-PD1 to treat tumor-bearing mice associated with colorectal cancer. ACY-1215 combined with anti-PD1 effectively inhibited the colorectal tumor growth. The expression of PD-L1 in tumor of mice were inhibited by ACY-1215 and anti-PD1 combination treatment, whereas some biomarkers reflecting T cell activation were upregulated. In a co-culture system of T cells and tumor cells, ACY-1215 helped T cells to kill tumor cells. Mechanically, HDAC6 enhanced the acetylation of STAT1 and inhibited the phosphorylation of STAT1, thus preventing STAT1 from entering the nucleus to activate PD-L1 transcription. This study reveals a novel regulatory mechanism of HDAC6 on non-histone substrates, especially on protein acetylation. HDAC6 inhibitors may be of great significance in tumor immunotherapy and related combination strategies.

Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer

“…In this study, the CT26 cells expressed 28.3 ± 3.2% of H2R and 9.4 ± 2.9% of PD-L1, which were not affected by cimetidine treatment in vitro. The surface expression of PD-L1 on other colon cancer cells, such as SW480 and HCT116, is 5.41 ± 0.06% and 2.77 ± 0.06%, respectively [ 38 ]. In our study, the surface expression of PD-L1 in CT26 cells was higher than that in the other colon cancer cell lines.…”

Histone Deacetylase 6 Inhibitor 5-Phenylcarbamoylpentyl Selenocyanide (SelSA) Suppresses Hepatocellular Carcinoma by Downregulating Phosphorylation of the Extracellular Signal-Regulated Kinase 1/2 Pathway

“…Consequently, the inhibition of HDAC6 has emerged as an efficacious therapeutic strategy for cancer, including HCC . Currently, a number of HDAC6 inhibitors have been developed, and ricolinostat (ACY-1215), citarinostat (ACY-241), KA2507, and CS3003 have entered clinical evaluations for cancer therapy. − However, to date, no HDAC6 inhibitors have been granted regulatory approval for clinical applications. Furthermore, the majority of reported HDAC6 inhibitors contain a hydroxamic acid as the zinc-binding group (ZBG), which typically exhibits moderate HDAC6 selectivity, instability, poor pharmacokinetics, and potential genotoxicity. , To address the aforementioned limitations, a range of nonhydroxamate ZBGs including 2-aminoanilide, α-ketoester, thiol, and hydrazide have been developed and evaluated.…”