BACKGROUND: The 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. METHODS: Whole-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. RESULTS: The 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. CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.
Aminopyridines/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , B7-H1 Antigen/metabolism , Benzamides/administration & dosage , Histone Deacetylase 1/genetics , Histone Deacetylase 2/genetics , Histone Deacetylases/genetics , Immune Checkpoint Inhibitors/administration & dosage , Liposarcoma/drug therapy , Aminopyridines/pharmacology , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Benzamides/pharmacology , Cell Line, Tumor , Gene Amplification , Gene Expression Profiling , Gene Expression Regulation, Neoplastic/drug effects , Humans , Immune Checkpoint Inhibitors/pharmacology , Liposarcoma/genetics , Liposarcoma/metabolism , Mice , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Sequence Analysis, RNA , Exome Sequencing , Xenograft Model Antitumor Assays
BACKGROUND: Unplanned excision (UPE) of soft tissue sarcoma (STS) is often chosen in the early phase by general physicians without any radiological evaluation. PURPOSE: The present study aimed to evaluate the impact of UPE on the clinical outcomes of patients with STS of the trunk and extremity. MATERIALS AND METHODS: Patients with STS of the trunk and extremity who underwent R0 resection between 1998 and 2016 were included and divided into the UPE and planned excision (PE) groups. Propensity score matching (PSM) was used to control the selection bias. The endpoints were disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS). RESULTS: In total, 458 patients (277 males, 181 females; median age: 43 years) were included: 329 (71.8%) in the PE group and 129 (28.2%) in the UPE group. The follow-up time ranged from 7.1 to 313.78 months, with a median of 112.18 months. UPE patients were more likely to have a smaller or superficial lesion and were more frequently administered adjuvant therapy. After PSM, compared with the PE group, the UPE group had a longer LRFS (P=0.015), but there was no difference between the two groups regarding DSS and MFS. Residual disease was observed in 77.5% of the re-resected specimens in the UPE group and was a risk factor for DSS (P = 0.046) and MFS (P = 0.029) but was not associated with local recurrence (LR) (P=0.475) or LRFS (P=0.334). Moreover, we found no difference in DSS, LRFS or MFS according to the interval from UPE to definitive resection. CONCLUSION: STS treated with UPE had distinct characteristics. Patients who undergo UPE followed by an additional wide R0 resection have similar oncological survival compared to patients who undergo an initial PE, although the high incidence of residual tumor in the UPE group leads to an unfavorable clinical course.
