Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma

Abstract

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Epigenetic Silencing of Immune-Checkpoint Receptors in Bone Marrow- Infiltrating T Cells in Acute Myeloid Leukemia

“…Several studies have demonstrated that treatment with HDACi dampens the anti-tumor immune response by upregulation of PD-1 on T cells ( 38 , 39 ). Thus, PD-1/PD-L1 blocking antibodies and HDACis have synergistic effects in the treatment of different cancers ( 38 , 39 ). Additionally, VPA treatment blocked the function of myeloid-derived suppressor cells and made tumor cells susceptible to anti-PD-L1 immunotherapy ( 40 ).…”

Glycogen Metabolism Predicts the Efficacy of Immunotherapy for Urothelial Carcinoma

“…By analyzing the drug sensitivity data, we speculated that HDAC inhibitors might enhance ICI efficacy and even reverse the poor response of low-GMS patients to ICI treatment, which was consistent with our GSEA results ( Figures 5A–C ). Some studies have reported HDAC inhibitors’ potential in enhancing the efficacy of immunotherapy and even reverse the insensitivity to ICI ( Ugurel et al, 2019 ) by enhancing the anti-tumor activity of CD8 + T cells ( Que et al, 2021 ) and NK cells ( Hicks et al, 2018 ; Kim et al, 2020 ), reducing the number of M2 macrophages ( Knox et al, 2019 ; Kim et al, 2020 ), impairing the immunosuppressive function of MDSCs ( Kim et al, 2020 ; Que et al, 2021 ) and increasing the expression of PD-L1 on tumor cells ( Hicks et al, 2018 ; Que et al, 2021 ). Two clinical studies investigated the efficacy of HDAC inhibitor vorinostat, combined with immunotherapy, demonstrating preliminary antitumor activity ( Gray et al, 2019 ; Rodriguez et al, 2020 ).…”

Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma

“…The other research group also reported the efficacy of HDAC inhibitor on liposarcoma cell lines by medium-scale high-throughput drug screening [41]. A recent study reported that the HDAC gene family was amplified in sarcomas, including in DDLPS, and that the combination of HDAC inhibitor and anti-PD1 therapy promoted tumor regression [42]. Another study suggested that HDAC inhibition reduced MDM2 expression and tumor growth in DDLPS [43].…”