本研究的目的是确定对 atezolizumab 加贝伐单抗 (ATZ  BV) 治疗有临床意义的生物标志物，并制定针对不可切除的肝细胞癌 (u-HCC) 的靶向策略。我们首先研究了循环肿瘤 DNA (ctDNA) 的潜力作为预测 24 名接受 ATZ  BV 治疗的 u-HCC 患者治疗结果的生物标志物。接下来，我们分析了 134 名接受 ATZ  BV 治疗的 u-HCC 患者血液样本中免疫相关细胞因子的水平。为此，HCC患者血清中已报道的血清免疫相关分子或癌症免疫周期相关分子，即CD274、LAG-3、CCL2、4、5、CXCL1、9、10、12、13、CX3CL1、使用酶联免疫吸附测定法测量 CCR5、IFNγ 和 IL-6, 8。在 TP53、APC、PIK3CA 和 VHL 中发现超过 1% 的变异读取频率 (VRF) 突变，尽管与治疗反应没有相关性。在评估的 15 种细胞因子中，ATZ  BV 治疗后客观缓解 (OR)、疾病稳定 (SD) 和疾病进展 (PD) 患者之间的 CXCL9 和 LAG-3 水平存在显着差异。 CXCL9（截止值：419.1 pg/ml）和 LAG-3（截止值：3736.3 pg/ml）的受试者工作特征曲线分析表明，区分 PD 和非 PD 的面积分别为 0.779 和 0.697和 OR 来自非 OR。在无进展生存期 (PFS) 和总生存期 (OS) 的多变量分析中，PFS 和总生存期 (OS) 的高血清 CXCL9（风险比 (HR) 和 95% 置信区间 (CI)：0.412 (0.251-0.677) (p = 0.0005)） OS 为 0.252 (0.125-0.508) (p = 0.0001)，PFS 为低血清 LAG-3（HR 和 95% CI 0.419 (0.249-0.705) (p = 0.0011)，PFS 为 0.294 (0.140-0.617) (p = 0.0012）为OS）是独立的阳性预测因素。虽然，据我们检查，没有发现血液中的ctDNA突变与ATZ  BV治疗效果、血清CXCL9和LAG-3水平相关，而这些水平与癌症相关-免疫周期，与治疗效果相关，并且可以作为 HCC 患者 ATZ  BV 治疗效果的预测标记。© 2024。亚太肝脏研究协会。

The aims of this study were to identify clinically significant biomarkers of a response to atezolizumab plus bevacizumab (ATZ + BV) therapy and to develop target strategies against unresectable hepatocellular carcinoma (u-HCC).We first investigated the potential of circulating tumor DNA (ctDNA) to serve as a biomarker for predicting the therapeutic outcome in 24 u-HCC patients treated with ATZ + BV therapy. Next, we analyzed levels of immune-related cytokines in blood samples from 134 u-HCC patients who received ATZ + BV. For this, serum immune-related molecules or cancer-immune cycle-related molecules that have been reported in HCC patient sera, namely CD274, LAG-3, CCL2, 4, 5, CXCL1, 9, 10, 12, 13, CX3CL1, CCR5, IFNγ and IL-6, 8 were measured using enzyme-linked immunosorbent assay.More than 1% of variant read frequency (VRF) mutations were found in TP53, APC, PIK3CA and VHL, although with no correlation with treatment response. Among the 15 cytokines evaluated, CXCL9 and LAG-3 levels were significantly different between patients with objective response (OR), stable disease (SD), and progressive disease (PD) following ATZ + BV treatment. Receiver-operating characteristic curve analyses of CXCL9 (cut-off value: 419.1 pg/ml) and LAG-3 (cut-off value: 3736.3 pg/ml) indicated areas of 0.779 and 0.697, respectively, for differentiating PD from non-PD and OR from non-OR. In multivariate analysis of progression-free survival (PFS) and overall survival (OS), high serum CXCL9 (hazard ratio (HR) and 95% confidence interval (CI): 0.412 (0.251-0.677) (p = 0.0005) for PFS and 0.252 (0.125-0.508) (p = 0.0001) for OS), and low serum LAG-3 (HR and 95% CI 0.419 (0.249-0.705) (p = 0.0011) for PFS and 0.294 (0.140-0.617) (p = 0.0012) for OS) were independent positive predictive factors.Although, as far as we examined, no ctDNA mutations in blood were found to be related to ATZ + BV treatment efficacy, serum CXCL9 and LAG-3 levels, which are related to the cancer-immune cycle, were associated with treatment efficacy and could be predictive markers of the efficacy of ATZ + BV treatment in HCC patients.© 2024. Asian Pacific Association for the Study of the Liver.