e16189 Background: The overall efficacy of immunotherapy for advanced biliary tract cancers (BTCs) was still poor, exploring the potential biomarkers associated with tumor response in advanced BTCs may further improve the clinical benefits from immunotherapy. Methods: Twelve patients from a phase 2 clinical trial (ChiCTR2000036652), which evaluated the efficacy and safety of sintilimab (anti-PD-1 antibody), plus gemcitabine and cisplatin as first-line treatment in advanced BTC patients, were included in the current biomarkers analysis. Exploratory points mainly focused on differentiated immune-related gene expression and immune pathway signatures using a 289-gene immune-related RNA panel sequencing on baseline tumor samples. Differential gene expression analysis was performed between responders (tumor regression) and non-responders (tumor extension) using Wilcoxon rank-sum test. Signature scores were calculated using the Gene Set Variation Analysis package with publicly available gene signatures. Results: Twelve patients (8 responders vs. 4 non-responders) who had available clinical response evaluations with RNA-sequencing data on baseline tumor samples were included in the current biomarkers analysis. Differential gene expression analysis revealed a significantly increased CXCL10, CXCL13 expression (p < 0.001) and decreased MAGEA12 expression (p < 0.001) in responder tumors compared with non-responder tumors. Differentiated genes were significantly enriched in cytokine-cytokine receptor interaction and interleukin-17 signaling pathway in responder tumors. Extensive analyses on immune pathway signatures showed that higher expression of IFN-γ-related genes (p = 0.048) and T cell-inflamed genes (p = 0.016) were associated with response to immunocombination therapy. Meanwhile, immune cell types score was also calculated, no notable differences were found between defined groups. Conclusions: Some differentially expressed genes were investigated in responder tumors compared with non-responder tumors. Higher expression of IFN-γ-related genes and T cell-inflamed genes could potentially predict the effect of immunocombination therapy. Potential biomarkers are needed to identify patients who respond to sintilimab plus gemcitabine and cisplatin in a larger validation cohort. Clinical trial information: ChiCTR2000036652.

Background The most part of primary liver cancer is hepatocellular carcinoma having a poor prognosis. The treatment strategies including multitarget inhibitors, ICIs, and new options are being explored. Recently studies demonstrated the synergistic effect of anti-angiogenesis-targeted drugs combined with immunotherapy. In this study, we explored toripalimab combined with anlotinib as second-line therapy to evaluate the safety and efficacy in advanced hepatocellular carcinoma (HCC). Patients and methods: Twenty-six patients diagnosed with HCC and experienced disease progression or drug intolerance after first-line targeted therapy were included in this study. All enrolled patients received toripalimab combined with anlotinib. The primary endpoint of this study was the objective response rate (ORR), secondary endpoints were progression-free survival (PFS), overall survival (OS), and disease control rates (DCR). Results Finally 22 patients met the protocol were included in the data analysis. The ORR was 7.69%, the mPFS was 3.12 months, mOS was 10.89 months, and DCR was 42.31%, among which 1 patient achieved CR, 1 patient achieved PR, and 9 patients achieved SD. By the last follow-up, the duration of CR in patients had been more than 2 years. No treatment-related deaths occurred, generally this combination therapy is well tolerated. Conclusion In patients who experience disease progression with first-line sorafenib or lenvatinib, toripalimab combined with anlotinib may be a good choice for second-line treatment and is well tolerated. TP53 mutations may serve as biomarkers for this treatment and larger sample size is required for further confirmation.

Hepatocellular carcinoma is a common tumor with a high fatality rate worldwide, and exploring its pathogenesis and deterioration mechanism is a focus for many researchers. Increasing evidence has shown that miRNAs are involved in the occurrence and progression of a variety of cancers, including hepatocellular carcinoma. Therefore, this study mainly aimed identify key miRNAs related to hepatocellular carcinoma and explore their potential functions and clinical significance. In this study, we performed miRNA sequencing on three pairs of hepatocellular carcinoma tissue samples and screened 26 differentially expressed miRNAs. Then 2 key miRNAs (miR-139-5p and miR-582-3p) were screened by Kaplan-Meier curve analysis, Cox multivariate analysis and qPCR methods. The expression of miR-582-3p was positively correlated with clinicopathological parameters in patients with hepatocellular carcinoma. Subsequently, miRwalk and starbase were used to predict the target genes of key miRNAs, and then the key pairs miR-582-3p/SMAD2 identified by WGCNA, PPI, qPCR and Pearson correlation analysis. Finally, a dual luciferase experiment, the rescue-of-function experiment and qPCR confirmed that miR-582-3p directly targets SMAD2 and regulates the proliferation, migration and invasion of HepG2 cells by targeting SMAD2. At the same time, interference with SMAD2 can influence the effect of miR-582-3p on HepG2 cells. In conclusion, our findings confirm that miR-582-3p is an independent factor for the prognosis of hepatocellular carcinoma patients, and can regulate the progression of hepatocellular carcinoma cells by targeting SMAD2.