Recent advances have enabled the direct induction of human tissue-specific stem and progenitor cells from differentiated somatic cells. However, it is not known whether human hepatic progenitor cells (hHepPCs) can be generated from other cell types by direct lineage reprogramming with defined transcription factors. Here, we show that a set of three transcription factors, FOXA3, HNF1A, and HNF6, can induce human umbilical vein endothelial cells to directly acquire the properties of hHepPCs. These induced hHepPCs (hiHepPCs) propagate in long-term monolayer culture and differentiate into functional hepatocytes and cholangiocytes by forming cell aggregates and cystic epithelial spheroids, respectively, under three-dimensional culture conditions. After transplantation, hiHepPC-derived hepatocytes and cholangiocytes reconstitute damaged liver tissues and support hepatic function. The defined transcription factors also induce hiHepPCs from endothelial cells circulating in adult human peripheral blood. These expandable and bipotential hiHepPCs may be useful in the study and treatment of human liver diseases.

Background and Aims: Durvalumab plus tremelimumab (Dur/Tre) therapy is expected to have good therapeutic efficacy for patients with unresectable hepatocellular carcinoma (u‐HCC). We previously reported that the neutrophil‐to‐lymphocyte ratio (NLR) during atezolizumab plus bevacizumab therapy in u‐HCC patients was a useful marker for predicting the therapeutic response. Therefore, we investigated whether the NLR during Dur/Tre therapy could predict treatment outcomes in patients with u‐HCC.Design: The present study included 64 u‐HCC patients treated with Dur/Tre and evaluated for their initial response by dynamic computed tomography or magnetic resonance imaging at least once until December 2024. Alpha‐fetoprotein (AFP) and des‐gamma‐carboxyprothrombin (DCP) ratios were defined as follows: the pretreatment levels of AFP and DCP were set to 1, and the AFP and DCP ratios to pretreatment were calculated at the start of the second course of Dur/Tre therapy.Results: Of the 64 HCC patients, 34 patients (53%) achieved a disease control rate (non‐PD) at the initial evaluation. The NLR at the start of the second course (NLR‐2c) tended to be lower in patients with non‐PD than progressive disease (p = 0.133), and the optimal cutoff value was 5.75. Patients with NLR‐2c ≥ 5.75 had a shorter progression‐free survival (PFS) than those with NLR‐2c < 5.75 (median: 1.7 vs. 5.5 months, p = 0.002). Multivariate analysis showed that NLR‐2c ≥ 5.75 (HR 4.66; p < 0.001) and AFP ratio ≥ 0.933 (HR 4.32; p = 0.004) were significantly associated with poor PFS.Conclusions: The NLR‐2c value is useful for predicting PFS in u‐HCC patients treated with Dur/Tre therapy.

We retrospectively evaluated the impact of therapeutic modifications of atezolizumab (Atezo) plus bevacizumab (Bev) therapy (Atezo/Bev), including the interruption or discontinuation of both Atezo and Bev, and the reduction or discontinuation of Bev, on the outcome of patients with unresectable hepatocellular carcinoma (uHCC) (median observation period: 9.40 months). One hundred uHCC from five hospitals were included. Therapeutic modifications without discontinuation of both Atezo and Bev (n = 46) were associated with favorable overall survival (median not reached; hazard ratio (HR): 0.23) and time to progression (median: 10.00 months; HR: 0.23) with no therapeutic modification defined as the reference. In contrast, the discontinuation of both Atezo and Bev without other therapeutic modifications (n = 20) was associated with unfavorable overall survival (median: 9.63 months; HR: 2.72) and time to progression (median: 2.53 months; HR: 2.78). Patients with modified albumin–bilirubin grade 2b liver function (n = 43) or immune-related adverse events (irAEs) (n = 31) discontinued both Atezo and Bev without other therapeutic modifications more frequently (30.2% and 35.5%, respectively) than those with modified albumin–bilirubin grade 1 (10.2%) and without irAEs (13.0%). Patients with objective response (n = 48) experienced irAEs more frequently (n = 21) than those without (n = 10) (p = 0.027). Avoiding the discontinuation of both Atezo and Bev without other therapeutic modifications may be the optimal management of uHCC.