Background/AimsHepatocellular carcinoma (HCC), accounting for 75-85% of primary liver cancer cases, is the third leading cause of cancer-related death worldwide. The purpose of this research was to examine the tumor immune microenvironment (TIME) in HCC.MethodsWe investigated the HCC TIME by integrated analysis of single-cell and bulk-tissue sequencing data to reveal the landscape of major immune cell types.ResultsRegulatory T(Treg) cells were found to be specifically distributed in the TIME of HCC. Several immune checkpoints, including TNFRSF4, TIGIT and CTLA4, were found to be uniquely overexpressed in Treg cells, and the glycolysis/gluconeogenesis pathway was enriched in Treg cells. We also discovered the presence of two NK-cell subsets with different cytotoxic capacities, one in an activated state with antitumor effects and another with an exhausted status. In addition, memory B cells in HCC were found to exist in a unique state, with high proliferation, low differentiation, and low activity, which was induced by overexpression of PRAP1 and activation of the MIF-CD74 axis.ConclusionsWe revealed the TIME landscape in HCC, highlighting the heterogeneity of major immune cell types and their potential mechanisms in the formation of an immunosuppressive environment. Hence, blocking the formation of the TIME could be a useful therapeutic strategy for HCC.

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e16126 Background: Results from the RESORCE-III RCT demonstrated that sequential sorafenib-regorafenib treatment significantly improved overall survival compared with the placebo group. However, there are no retrospective studies of regorafenib as a first-line agent for treating patients with advanced hepatocellular carcinoma in a real-world setting. Therefore, we aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with immune checkpoint inhibitors (ICIs) in treating patients with advanced hepatocellular carcinoma in a real-world setting. Methods: We reviewed medical data from 48 patients with advanced hepatocellular carcinoma treated with regorafenib as a first-line agent alone or combined with ICIs between December 2018 and February 2022. These patients were treated with regorafenib for at least 28 consecutive days (21 days on and 7 days off the drug). The progression-free survival (PFS), overall survival (OS), objective response rate (ORR, RECIST 1.1 criteria) and disease control rate (DCR) were observed. Results: A total of 48 patients were enrolled in this study, 26(54.2%) receiving regorafenib as monotherapy and 22(45.8%) receiving the combination ICIs. The median age in the monotherapy group was 54 years (range 38-74), male/female (69.2%/30.8%), BCLC stage B/C (42.3%/57.7%), Child-Pugh A/B score (57.7%/42.3%); the median age in the combined ICIs group was 53 years (range 42-75), male/female (68.2%/ 31.8%), BCLC stage B/C (36.4%/63.6%), Child-Pugh A/B score (54.5%/45.5%). Median PFS (mPFS) was 7.7 months (95% CI:5.9-10.4) and median OS (mOS) was 16.7 months (95% CI:14.3-23.6) in 48 patients. In the regorafenib monotherapy group, mPFS was 5.9 months (95% CI:5.6-10.3) and mOS was 13.9 months (95% CI:13.5-22.5); in the combined ICIs group, mPFS was 7.8 months (95% CI:7.3-14.5) and mOS was 23.6 months (95% CI:16.6-NA). The ORR and DCR were 20.8% and 72.9% in the overall treatment group, 15.4% and 65.4% in the monotherapy group, and 27.3% and 81.8% in the combined ICIs treatment group, respectively. Among the adverse events, rates were 34.6% (9/26) and 36.4% (8/22) in the monotherapy and combined ICIs groups, respectively, with only one grade III/IV adverse event in the monotherapy group and no grade III/IV adverse event in the combined ICIs group. Conclusions: This retrospective, real-world, preliminary study demonstrates that regorafenib as a first-line agent alone or in combination with ICIs has a high safety profile and more prolonged survival in patients with advanced hepatocellular carcinoma, particularly in combination with ICIs.

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