Cho Hee Sun, Lee Soon Kyu, Han Ji Won, Kwon Jung Hyun, Nam Soon Woo, Lee Jaejun, Yang Keungmo, Sung Pil Soo, Jang Jeong Won, Yoon Seung Kew, Choi Jong Young
The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Department of Internal Medicine, College of Medicine, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
Front Immunol. 2025 Jun 11;16:1578422. doi: 10.3389/fimmu.2025.1578422. eCollection 2025.
Several serum cytokines have been proposed as biomarkers for predicting the outcomes of patients with hepatocellular carcinoma (HCC) receiving tyrosine kinase inhibitors. However, their role in atezolizumab plus bevacizumab (AB) treatment needs to be more elucidated.
We examined various serum cytokines, including interferon-γ (IFN-γ), interleukin-10 (IL-10), IL-12, IL-17, IL-2, IL-6, and tumor necrosis factor, using a Luminex cytokine multiplex assay before AB treatment in prospectively enrolled 116 AB-treatment patients for the derivation cohort and 54 patients for the external validation cohort. We collected baseline characteristics, including neutrophil-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels, and prospectively observed clinical outcomes.
Among various peripheral blood inflammatory markers, high NLR, CRP, IL-2, and IL-12 levels were significantly associated with poor progression-free survival (PFS) and overall survival (OS) in patients with AB-treated HCC. Through sensitivity analysis, we defined the high peripheral blood inflammatory score (PBIS) group, which included two or more of the following elevated factors: NLR, CRP, IL-2, and IL-12. The high PBIS group had elevated serum inflammatory cytokines and a higher tumor burden than the low PBIS group. A high PBIS score was an independent risk factor associated with poor OS, PFS, and objective response rate (ORR) in multivariate analyses, which was also confirmed in the validation cohort and propensity score-matched cohort. However, it was not a significant factor for OS, PFS, or ORR in lenvatinib-treated patients.
These results suggest that a peripheral blood marker-based scoring system can significantly predict clinical outcomes in patients with AB-treated HCC. This non-invasive biomarker is expected to be a potential predictive and prognostic factor for AB treatment.
几种血清细胞因子已被提议作为预测接受酪氨酸激酶抑制剂治疗的肝细胞癌（HCC）患者预后的生物标志物。然而，它们在阿替利珠单抗联合贝伐单抗（AB）治疗中的作用尚需进一步阐明。
我们使用Luminex细胞因子多重检测法，在AB治疗前检测了前瞻性纳入的116例AB治疗患者（推导队列）和54例患者（外部验证队列）的多种血清细胞因子，包括干扰素-γ（IFN-γ）、白细胞介素-10（IL-10）、IL-12、IL-17、IL-2、IL-6和肿瘤坏死因子。我们收集了基线特征，包括中性粒细胞与淋巴细胞比值（NLR）和C反应蛋白（CRP）水平，并前瞻性观察临床结局。
在各种外周血炎症标志物中，高NLR、CRP、IL-2和IL-12水平与接受AB治疗的HCC患者的无进展生存期（PFS）和总生存期（OS）显著相关。通过敏感性分析，我们定义了高外周血炎症评分（PBIS）组，该组包括以下两种或更多升高的因素：NLR、CRP、IL-2和IL-12。高PBIS组的血清炎症细胞因子升高，肿瘤负荷高于低PBIS组。在多变量分析中，高PBIS评分是与OS、PFS和客观缓解率（ORR）差相关的独立危险因素，这在验证队列和倾向评分匹配队列中也得到了证实。然而，在接受乐伐替尼治疗的患者中，它不是OS、PFS或ORR的显著因素。
这些结果表明，基于外周血标志物的评分系统可以显著预测接受AB治疗的HCC患者的临床结局。这种非侵入性生物标志物有望成为AB治疗的潜在预测和预后因素。
