Ueshima Eisuke, Sofue Keitaro, Kodama Takahiro, Yamamoto Shuhei, Komatsu Masato, Komatsu Shohei, Ishihara Nobuaki, Umeno Akihiro, Yamaguchi Takeru, Hori Masatoshi, Fukumoto Takumi, Takehara Tetsuo, Murakami Takamichi
Department of Radiology, Kobe University Graduate School of Medicine, Kobe, Japan.
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka, Japan.
Liver Cancer. 2024 Nov 13;14(3):271-285. doi: 10.1159/000542099. eCollection 2025 Jun.
Immunotherapy is the first-line treatment for intermediate-advanced stage hepatocellular carcinoma (HCC), although its outcomes vary. This study aimed to identify imaging biomarkers of immunotherapy susceptibility linked to gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and immune phenotypes, particularly immune-excluded phenotypes, with a tumor immune barrier.
We performed immunohistochemical staining with a CD8 antibody, and samples were classified into immune-inflamed, -intermediate, -excluded, and -ignored phenotypes. We assessed EOB-MRI findings obtained from 104 patients who underwent hepatectomy for HCC and evaluated the relationship between MRI findings and immune phenotype. Spatial transcriptome analysis of tumor tissues in each immune phenotype was performed to characterize the MRI findings. For validation, we analyzed the treatment effect on 60 nodules in another cohort of 27 patients who received combined immunotherapy using anti-programmed death-ligand 1 and anti-vascular endothelial growth factor (VEGF) antibodies.
HCCs with rim arterial phase hyperenhancement (APHE) (odds ratio [OR] 17.3, = 0.009), peritumoral enhancement in the arterial phase (OR: 8.6, < 0.004), and intermediate intensity on the hepatobiliary phase (HBP) measured with a visual 3-point scale (OR: 28.2, = 0.002) were associated with immune-excluded phenotype, where tumors tended to be larger and of the single nodular type with extranodular growth and confluent multinodular rather than the simple nodular type. Spatial transcriptome analysis revealed a spatial relationship among cytotoxic T lymphocytes, VEGF signals, and cancer-associated fibroblasts at the tumor-invasive margins in this phenotype. From the validation study, nodules with any one of these three imaging findings had a significantly prolonged time to-nodular progression ( = 0.007, median not reached vs. 226 days).
HCCs with rim APHE, peritumoral enhancement in arterial phase, and intermediate intensity on HBP with visual 3-point scale could be non-invasive biomarkers to predict the immune-excluded phenotype with the tumor immune barrier. These HCCs were most likely to respond to combined immunotherapy.
免疫疗法是中晚期肝细胞癌（HCC）的一线治疗方法，但其疗效各异。本研究旨在确定与钆塞酸增强磁共振成像（EOB-MRI）和免疫表型相关的免疫疗法敏感性的影像学生物标志物，特别是具有肿瘤免疫屏障的免疫排除表型。
我们用CD8抗体进行免疫组化染色，并将样本分为免疫炎症型、中间型、排除型和忽略型表型。我们评估了104例因HCC接受肝切除术的患者的EOB-MRI结果，并评估了MRI结果与免疫表型之间的关系。对每种免疫表型的肿瘤组织进行空间转录组分析，以表征MRI结果。为了进行验证，我们分析了另一组27例接受抗程序性死亡配体1和抗血管内皮生长因子（VEGF）抗体联合免疫治疗的患者中60个结节的治疗效果。
边缘动脉期高增强（APHE）的HCC（优势比[OR] 17.3，P = 0.009）、动脉期瘤周增强（OR：8.6，P < 0.004）以及用视觉3分法测量的肝胆期（HBP）中等强度（OR：28.2，P = 0.002）与免疫排除表型相关，在该表型中肿瘤往往更大，呈单结节型，有结节外生长和融合性多结节，而非单纯结节型。空间转录组分析揭示了该表型中肿瘤侵袭边缘的细胞毒性T淋巴细胞、VEGF信号和癌症相关成纤维细胞之间的空间关系。在验证研究中，具有这三种影像表现中任何一种的结节至结节进展时间显著延长（P = 0.007，中位数未达到 vs. 226天）。
具有边缘APHE、动脉期瘤周增强以及视觉3分法测量的HBP中等强度的HCC可能是预测具有肿瘤免疫屏障的免疫排除表型的非侵入性生物标志物。这些HCC最有可能对联合免疫疗法有反应。
