Hepatology communications · 2026
Spatiotemporal dynamics of the tumor microenvironment in hepatocellular carcinoma during combination immunotherapy.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Iwasaki Hitoshi, Itoh Shinji, Toshida Katsuya, Mita Junya, Ishikawa Takuma, Iseda Norifumi, Yugawa Kyohei, Yoshiya Shohei, Motomura Takashi, Toshima Takeo, Aishima Shinichi, Oda Yoshinao, Yoshizumi Tomoharu
Аннотация
BACKGROUND: Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood.
METHODS: We performed single-cell RNA sequencing of paired hepatectomy specimens obtained before and after ATZ/BEV from one patient and of tumor center and margin samples from another patient after ATZ/BEV. Cell composition, subclusters, and cell-cell communication were analyzed. In addition, candidate molecules identified by transcriptomic analysis were further assessed using serum-based assays and immunohistochemistry.
RESULTS: These single-cell analyses suggested that ATZ/BEV was associated with a shift toward an immune-active tumor microenvironment, with increased CD8+ T cells together with reduced endothelial cells. CD8+ T cells showed increased effector and exhaustion signatures, indicating coexistence of activation and dysfunction. CellChat analysis demonstrated selective activation of the TIGIT-PVR/NECTIN2 axis after treatment. Spatial analysis showed that the tumor margin was enriched for CD8+ T cells and exhibited stronger effector and exhaustion activity than the tumor center. Immunoregulatory signaling was also more prominent at the margin. Serum TIGIT levels were significantly higher after ATZ/BEV than in upfront resection cases (p=0.0325). Immunohistochemistry showed greater margin-to-center differences in TIGIT (p=0.0019) and PVR (p=0.0008) in the tumor after ATZ/BEV.
CONCLUSIONS: Our exploratory findings suggest that ATZ/BEV may remodel the HCC microenvironment toward a state characterized by concurrent CD8+ T-cell activation and inhibitory signaling through the TIGIT-PVR/NECTIN2 axis, particularly at the tumor margin.
METHODS: We performed single-cell RNA sequencing of paired hepatectomy specimens obtained before and after ATZ/BEV from one patient and of tumor center and margin samples from another patient after ATZ/BEV. Cell composition, subclusters, and cell-cell communication were analyzed. In addition, candidate molecules identified by transcriptomic analysis were further assessed using serum-based assays and immunohistochemistry.
RESULTS: These single-cell analyses suggested that ATZ/BEV was associated with a shift toward an immune-active tumor microenvironment, with increased CD8+ T cells together with reduced endothelial cells. CD8+ T cells showed increased effector and exhaustion signatures, indicating coexistence of activation and dysfunction. CellChat analysis demonstrated selective activation of the TIGIT-PVR/NECTIN2 axis after treatment. Spatial analysis showed that the tumor margin was enriched for CD8+ T cells and exhibited stronger effector and exhaustion activity than the tumor center. Immunoregulatory signaling was also more prominent at the margin. Serum TIGIT levels were significantly higher after ATZ/BEV than in upfront resection cases (p=0.0325). Immunohistochemistry showed greater margin-to-center differences in TIGIT (p=0.0019) and PVR (p=0.0008) in the tumor after ATZ/BEV.
CONCLUSIONS: Our exploratory findings suggest that ATZ/BEV may remodel the HCC microenvironment toward a state characterized by concurrent CD8+ T-cell activation and inhibitory signaling through the TIGIT-PVR/NECTIN2 axis, particularly at the tumor margin.