A high rate of recurrence after curative therapy is a major challenge for the management of hepatocellular carcinoma (HCC). Currently, no effective adjuvant therapy is available to prevent HCC recurrence. We designed a personalized neoantigen-loaded dendritic cell vaccine and neoantigen-activated T-cell therapy, and used it as adjuvant therapy to treat 10 patients with HCC who had undergone curative resection or radiofrequency ablation in the first stage of a phase II trial (NCT03067493). The primary outcomes were safety and neoantigen-specific immune response. Disease-free survival (DFS) was also evaluated. The immunotherapy was successfully administered to all the patients without unexpected delay and demonstrated a reasonable safety profile with no grade ≥3 treatment-related side effects reported. Seventy percent of patients generated de novo circulating multiclonal neoantigen-specific T-cell responses. Induced neoantigen-specific immunity was maintained over time, and epitope spreading was observed. Patients who generated immune responses to treatment exhibited prolonged DFS compared with nonresponders (P = 0.012), with 71.4% experiencing no relapse for 2 years after curative treatment. High expression of an immune stimulatory signature, enhanced immune-cell infiltration (i.e., CD8+ T cells), and upregulated expression of T-cell inflammatory gene profiles were found in the primary tumors of the responders. In addition, neoantigen depletion (immunoediting) was present in the recurrent tumors compared with the primary tumors (7/9 vs. 1/17, P = 0.014), suggesting that immune evasion occurred under the pressure of immunotherapy. Our study indicates that neoantigen-based combination immunotherapy is feasible, safe, and has the potential to reduce HCC recurrence after curative treatment.

Although cathepsin C (CTSC) has been reported to maintain malignant biological properties in various cancers, its functions in hepatocellular carcinoma (HCC) remain obscure. We aimed to investigate the potential role of CTSC in HCC. HCC tissue microarrays (n=122) were employed to analyze the correlation between CTSC expression and clinicopathological characteristics through immunohistochemistry staining. Quantitative real-time polymerase chain reaction, western blot assay, Cell Counting Kit-8 assay, colony formation, cell migration, and invasion assays, xenograft mice model were adopted to validate what had been indicated by the bioinformatic web tools. By bioinformatic tools and tissue microarrays, CTSC was found upregulated in HCC compared with normal liver tissues, and its higher expression was correlated with poor prognosis of HCC patients (hazard ratio, 2.402; 95% confidence interval, 1.493 to 3.865; p < 0.001). By gain/loss-of-function assays, we implicated that CTSC functioned as an oncogene to promote the proliferation and metastasis of HCC cells. Mechanistically, we revealed that CTSC was involved in several cancer-related signaling pathways by Gene Set Enrichment Analysis, among which tumor necrosis factor α (TNF-α)/p38 pathway was verified to be activated by CTSC. Furthermore, we found that TNF-α could activate CTSC expression in a concentration- dependent manner. Ralimetinib, an oral p38 mitogen-activated protein kinase (MAPK) inhibitor could inhibit CTSC expression. These indicated a potential positive feedback loop between CTSC and TNF-α/MAPK (p38) signaling. Taken together, CTSC plays an important role in the growth and metastasis of HCC and may be a promising therapeutic target upon HCC.

Intrahepatic cholangiocarcinoma (ICC) is a deadly cancer with rapid tumor progression. While hyperactive mRNA translation caused by mis-regulated mRNA or tRNA modifications promotes ICC development, the role of rRNA modifications remains elusive. Here, we found that 18S rRNA m⁶A modification and its methyltransferase METTL5 were aberrantly upregulated in ICC and associated with poorer survival (Log rank test, p<0.05). We further revealed the critical role of METTL5-mediated 18S rRNA m⁶A modification in regulation of ICC cell growth and metastasis using loss- and gain-of function assays in vitro and in vivo. The oncogenic function of METTL5 is corroborated using liver-specific knockout and overexpression ICC mouse models. Mechanistically, METTL5 depletion impairs 18S rRNA m⁶A modification that hampers ribosome synthesis and inhibits translation of G-quadruplexes-containing mRNAs that enriched in TGF-beta pathway. Our study uncovers the important role of METTL5-mediated 18S rRNA m⁶A modification in ICC and unravels the mechanism of rRNA m⁶A modification-mediated oncogenic mRNA translation control.

Physiologic roles of copper in metabolic homeostasis have been well established; however, whether and how copper is dysregulated in tumors and contributes to tumorigenesis is not recapitulated. Here, we comprehensively summarize the potential origins of copper accumulation in diseases, especially in cancers, by dysregulating copper transporter 1 (CTR1) or ATPase copper transporting alpha/beta (ATP7A/B) and further demonstrate the underlying mechanism of copper contributing to tumorigenesis. Specifically, in addition to modulating reactive oxygen species (ROS), angiogenesis, immune response, and metabolic homeostasis, copper recently has drawn more attention by directly binding to oncoproteins such as MEK, ULK, Memo, and PDK1 to activate distinct oncogenic signals and account for tumorigenesis. In the end, we disclose the emerging applications of copper in cancer diagnosis and highlight the promising strategies to target the copper–CTR1 axis for cancer therapies.

Purpose: The patterns and risk factors of postsurgical recurrence of patient with hepatocellular carcinoma (HCC) with microvascular invasion (MVI) are not clarified. This study aimed to decipher and compare the postoperative recurrent patterns and the risk factors contributing to recurrence between MVI positive (MVI⁽⁺⁾) and MVI negative (MVI^(-)) HCC after hepatectomy. Patients and methods: Patients with HCC who underwent hepatectomy in three Chinese academic hospitals between January 1, 2009, and December 31, 2018, were enrolled. Recurrent patterns included early (≤ 2 years) or late (> 2 years) recurrence, recurrent sites and number, and risk factors of recurrence were compared between the MVI⁽⁺⁾and MVI^(-) groups by propensity score–matching (PSM). Results: Of 1756 patients included, 581 (33.1%) were MVI⁽⁺⁾, and 875 (49.8%) patients developed early recurrence. Compared with the MVI^(-) group, the MVI⁽⁺⁾ group had a higher 2-year recurrence rate in the PSM cohort (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.59– 2.10; P < 0.001), and more patients with multiple tumor recurrence. Patients with early recurrence in the MVI⁽⁺⁾ group had a worse overall survival (OS) than those in the MVI^(-) group (HR, 1.24; 95% CI, 1.02– 1.50; P = 0.034). Resection margin (RM) ≤ 1.0 cm is a surgical predictor of early recurrence for the MVI⁽⁺⁾ group (HR, 0.68; 95% CI, 0.54– 0.87; P = 0.002), but not for the MVI^(-) group. Conclusion: Compared to MVI^(-) HCC, MVI⁽⁺⁾ HCC tends to be early, multiple recurrence and lung and lymph node metastasis after resection. RM ≤ 1.0 cm is a surgical risk factor of early recurrence for patient with MVI.