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Simple Summary: Circulating tumor cells (CTCs) derived from peripheral blood have a notable advantage in that they are noninvasive and real-time biomarkers and have attracted attention in monitoring therapeutic efficacy. Combination immunotherapy has promising outcomes in patients with unresectable hepatocellular carcinoma (HCC). However, there is no reliable biomarker for predicting disease progression. In this study, CTCs were serially collected from HCC patients undergoing atezolizumab plus bevacizumab (Atezo+Bev). Changes in CTC numbers during Atezo+Bev treatment reflected the tumor volume, and patients with elevated transforming growth factor (TGF)-β signaling molecules had a poorer response, whereas those with elevated apoptosis signaling molecules had a favorable response. This highlights that changes in the expression of TGF-β molecules of CTCs could serve as novel biomarkers for the early prediction of therapeutic response in patients with unresectable HCC undergoing Atezo+Bev. Immune checkpoint inhibitors have promising outcomes in patients with hepatocellular carcinoma (HCC); however, there is no reliable biomarker for predicting disease progression. Circulating tumor cells (CTCs) derived from peripheral blood have attracted attention in monitoring therapeutic efficacy. In this study, CTCs were serially collected from HCC patients undergoing atezolizumab plus bevacizumab (Atezo+Bev), and changes in molecular expression and CTC numbers were analyzed to identify effective biomarkers. Changes in CTC numbers during Atezo+Bev reflected the tumor volume. Targeted RNA sequencing with next-generation sequencing (NGS) revealed that patients with elevated transforming growth factor (TGF)-β signaling molecules had a poorer response, whereas those with elevated apoptosis signaling molecules had a favorable response. In addition, compared with changes in CTC counts, changes in TGF-β signaling molecule expression in CTCs accurately and promptly predicted treatment response. Overall, NGS analysis of CTC-derived RNA showed that changes in TGF-β signaling molecules predict treatment response earlier than changes in CTC counts. These findings suggest that changes in the expression of TGF-β molecules in CTCs could serve as novel biomarkers for the early prediction of therapeutic response in patients with unresectable HCC undergoing Atezo+Bev. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) represents a significant health challenge, demanding innovative approaches for effective treatment. Despite advances in immune checkpoint inhibitor (ICI) therapy, reliable biomarkers to predict treatment response in HCC have yet to be found. Our study addressed this critical research gap by exploring the role of circulating tumor cells (CTCs) and their PD-L1 RNA expression in predicting response to atezolizumab and bevacizumab (Atezo/Bev) treatment. CTC-derived RNA collected serially during Atezo/Bev treatment suggests that patients with higher levels of PD-L1 expression in CTCs at baseline were more responsive to this treatment, but not lenvatinib treatment. Moreover, PD-L1 RNA levels in CTCs were an accurate response predictor and a monitorable biomarker that changed dynamically to reflect the response during Atezo/Bev treatment. The results of this study highlight the potential for individualized treatment decisions based on PD-L1 expression in CTCs and have implications for clinical practice. There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment. [ABSTRACT FROM AUTHOR]

Aim: Curing hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA (cccDNA). Interferon (IFN)‐γ has noncytolytic antiviral potential; however, elimination of cccDNA could not be achieved. To enhance the regulatory effect, we comprehensively analyzed the host factors associated with cccDNA amplification and IFN‐γ and IFN‐α effects using an in vitro HBV infection system showing various transcription levels. Methods: Primary human hepatocytes were infected with HBV using genomic plasmids carrying the basic core promoter mutation A1762T/G1764A and/or the precore mutation G1896A and treated with IFN‐γ and IFN‐α. Comprehensive and functional studies involving microarray and small interfering RNA analysis revealed the host factors related to cccDNA regulation. Results: The HBV infection system reproduced the HBV life cycle and showed various propagation levels. Microarray analysis revealed 53 genes correlated with the cccDNA levels. Of the 53 genes, expression of IFN‐induced protein 44‐like (IFI44L) was significantly upregulated by IFN‐γ and IFN‐α. The anti‐HBV effect of IFI44L is exerted regardless of IFN‐γ or IFN‐α by inhibiting the activation of nuclear factor‐κB and signal transducer and activator of transcription 1 pathways. Conclusions: Using the in vitro HBV infection system, an IFN‐inducible molecule, IFI44L, associated with cccDNA amplification, was identified. These results suggest an innovative molecular strategy for the regulation of HBV cccDNA by controlling a novel host factor, IFI44L. [ABSTRACT FROM AUTHOR]