Transarterial chemoembolization (TACE) is the major treatment for advanced hepatocellular carcinoma (HCC), but it may cause hypoxic environment, leading to rapid progression after treatment. Here, using high-throughput sequencing on different models, S100 calcium binding protein A9 (S100A9) is identified as a key oncogene involved in post-TACE progression. Depletion or pharmacologic inhibition of S100A9 significantly dampens the growth and metastatic ability of HCC. Mechanistically, TACE induces S100A9 via hypoxia-inducible factor 1𝜶 (HIF1A)-mediated pathway. S100A9 acts as a scaffold recruiting ubiquitin specific peptidase 10 and phosphoglycerate mutase family member 5 (PGAM5) to form a tripolymer, causing the deubiquitination and stabilization of PGAM5, leading to mitochondrial fission and reactive oxygen species production, thereby promoting the growth and metastasis of HCC. Higher S100A9 level in HCC tissue or in serum predicts a worse outcome for HCC patients. Collectively, this study identifies S100A9 as a key driver for post-TACE HCC progression. Targeting S100A9 may be a promising therapeutic strategy for HCC patients.

No abstract

Background: The long-term survival of patients with hepatocellular carcinoma (HCC) with portal vein tumour thrombus (PVTT) is poor. Systemic therapy, transcatheter arterial chemoembolization (TACE), and hepatic artery infusion chemotherapy are widely used in HCC patients with PVTT. This study aims to explore the efficacy of combining systemic therapy with transarterial-based therapy in HCC patients with PVTT. Materials and methods: The authors retrospectively reviewed data of HCC patients with PVTT treated with combination therapy (TACE-hepatic artery infusion chemotherapy with tyrosine kinase inhibitors and PD-1 inhibitors) or TACE alone in SYSUCC from 2011 to 2020. The overall survival (OS), progression-free survival, and overall response rate were compared. Propensity score matching was used to minimize confounding bias. Results: A total of 743 HCC patients with PVTT received combination therapy (n=139) or TACE alone (n=604). After propensity score matching, the overall response rate was significantly higher in the combination group than in the TACE group [42.1% vs. 5.0%, P < 0.001 (response evaluation criteria in solid tumours); 53.7% vs. 7.8%, P < 0.001 (modified response evaluation criteria in solid tumours)]. The combination group showed significantly better OS than the TACE group (median OS not reached vs. 10.4 months, P < 0.001). The median progression-free survival of the combination and TACE groups was 14.8 and 2.3 months (P < 0.001), respectively. Tumour downstaging followed by salvage liver resection was significantly more common for the combination therapy group than for TACE group (46.3% vs. 4.5%, P < 0.001). After salvage liver resection, 31.6% (30/95) and 1.7% (3/179) of the patients achieved a pathological complete response in the combination and TACE groups, respectively (P < 0.001). The grade 3/4 adverse events rates were similar between the two groups (28.1% vs. 35.9%, P=0.092). Conclusion: Compared with TACE alone, combination therapy was safe enough and resulted in survival benefits. This is a promising treatment option for HCC patients with PVTT.

Background Non-homologous DNA end joining (NHEJ) is the predominant DNA double-strand break (DSB) repair pathway in human. However, the relationship between NHEJ pathway and hepatocellular carcinoma (HCC) is unclear. We aimed to explore the potential prognostic role of NHEJ genes and to develop an NHEJ-based prognosis signature for HCC. Methods Two cohorts from public database were incorporated into this study. The Kaplan–Meier curve, the Least absolute shrinkage and selection operator (LASSO) regression analysis, and Cox analyses were implemented to determine the prognostic genes. A NHEJ-related risk model was created and verified by independent cohorts. We derived enriched pathways between the high- and low-risk groups using Gene Set Enrichment Analysis (GSEA). CIBERSORT and microenvironment cell populations-counter algorithm were used to perform immune infiltration analysis. XRCC6 is a core NHEJ gene and immunohistochemistry (IHC) was further performed to elucidate the prognostic impact. In vitro proliferation assays were conducted to investigate the specific effect of XRCC6. Results A novel NHEJ-related risk model was developed based on 6 NHEJ genes and patients were divided into distinct risk groups according to the risk score. The high-risk group had a poorer survival than those in the low-risk group (P < 0.001). Meanwhile, an obvious discrepancy in the landscape of the immune microenvironment also indicated that distinct immune status might be a potential determinant affecting prognosis as well as immunotherapy reactiveness. High XRCC6 expression level associates with poor outcome in HCC. Moreover, XRCC6 could promote HCC cell proliferation in vitro. Conclusions In brief, this work reveals a novel NHEJ-related risk signature for prognostic evaluation of HCC patients, which may be a potential biomarker of HCC immunotherapy.

Background & aims: The application of immunotherapy in hepatocellular carcinoma has been hindered by resistance to therapeutics. Cancer cell-induced CD8+ T cell malfunction may account for the failure of tumor immunotherapies. The crucial regulators in HCC that mediate resistance to CD8+ T cell-based cancer immunotherapy are still obscure. Methods: Three independent CRISPR genome-wide screening was constructed. HCC cell-CD8+T cell co-culture model and mouse HCC models were performed to explore the effect of cancer USP14 in vitro and in vivo. Metabolomics, glucose up-take analysis and immune co-precipitation were performed for mechanismstudy. scRNA-seq, HCC PDO and PDX models were used to validate the therapeutic potential of targeting cancer USP14. Results: USP14 was identified as an essential driver of HCC cells tolerating to CD8+ T cells. Cancer USP14 was upregulated and positively correlated with resistance to anti-PD1 therapy and poor prognoses in HCC patients. Inhibition of cancer USP14 reduced the growth of HCC cell with CD8+ T cell co-culturing and enhanced the function of co-cultured CD8+ T cells. Targeting cancer USP14 inhibited HCC tumor growth and boosted anti-PD1-induced tumor immunity in vivo. USP14 highly-expressed HCC cells were avidly consumed and outcompeted CD8+ T cells for glucose by stabilizing GLUT1, resulting in CD8+ T cells starving and malfunction. These HCC cells also lead to acidification in the TME, causing CD8+ T cell dysfunction. The PDO and PDX models confirmed the above results. Conclusions:Our data defined a pro-immunoevasiverole for cancer USP14 in CD8+ T cell-based tumor immunity. Combining USP14 inhibition and PD1 blockade constitutes a potential therapy for HCC. Lay summary: Cancer USP14 sever as a potential therapeutic target for HCC.