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Abstract：
UNASSIGNED: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev).
UNASSIGNED: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing.
UNASSIGNED: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment.
UNASSIGNED: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.
UNASSIGNED: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.
UNASSIGNED: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing.
UNASSIGNED: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment.
UNASSIGNED: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.
UNASSIGNED: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.
摘要：
UNASSIGNED：我们阐明了阿特珠单抗和贝伐单抗（Ate/Bev）治疗的不可切除肝细胞癌（HCC）患者血清IL-6水平的临床和免疫学意义。
UNASSIGNED：我们前瞻性招募了165例不可切除的HCC患者（发现队列：来自三个中心的84例患者；验证队列：来自一个中心的81例患者）。使用流式细胞术珠子阵列分析基线血液样品。使用RNA测序分析肿瘤免疫微环境。
UNASSIGNED：在发现队列中，临床获益6个月（CB6m）定义为完全或部分缓解，或病情稳定≥6个月。在各种基于血液的生物标志物中，无CB6m的参与者的血清IL-6水平显着高于有CB6m的参与者（平均11.56vs.5.05pg/ml,p=0.02)。使用最大程度地选择排名统计信息，高IL-6的最佳临界值确定为18.49pg/ml，15.2%的参与者在基线时发现IL-6水平较高.在发现和验证队列中，与基线IL-6水平较低的参与者相比,基线IL-6水平较高的参与者在Ate/Bev治疗后的缓解率降低,无进展生存期和总生存期较差.在多变量Cox回归分析中，高IL-6水平的临床意义持续存在，即使在调整了各种混杂因素之后。IL-6水平高的参与者显示CD8T细胞分泌的干扰素-γ和肿瘤坏死因子-α减少。此外，过量的IL-6抑制细胞因子的产生和CD8+T细胞的增殖。最后,IL-6水平高的参与者表现出非T细胞炎症的免疫抑制肿瘤微环境.
UASSIGNED：在Ate/Bev治疗后，高基线IL-6水平可能与不良临床结局和T细胞功能受损相关。
UNASSIGNED：尽管对阿特珠单抗和贝伐单抗治疗有反应的肝细胞癌患者表现出良好的临床结局，其中一小部分仍然存在主要阻力。我们发现，在接受阿特珠单抗和贝伐单抗治疗的肝细胞癌患者中，高基线血清IL-6水平与不良临床结果和T细胞反应受损相关。
UNASSIGNED：我们前瞻性招募了165例不可切除的HCC患者（发现队列：来自三个中心的84例患者；验证队列：来自一个中心的81例患者）。使用流式细胞术珠子阵列分析基线血液样品。使用RNA测序分析肿瘤免疫微环境。
UNASSIGNED：在发现队列中，临床获益6个月（CB6m）定义为完全或部分缓解，或病情稳定≥6个月。在各种基于血液的生物标志物中，无CB6m的参与者的血清IL-6水平显着高于有CB6m的参与者（平均11.56vs.5.05pg/ml,p=0.02)。使用最大程度地选择排名统计信息，高IL-6的最佳临界值确定为18.49pg/ml，15.2%的参与者在基线时发现IL-6水平较高.在发现和验证队列中，与基线IL-6水平较低的参与者相比,基线IL-6水平较高的参与者在Ate/Bev治疗后的缓解率降低,无进展生存期和总生存期较差.在多变量Cox回归分析中，高IL-6水平的临床意义持续存在，即使在调整了各种混杂因素之后。IL-6水平高的参与者显示CD8T细胞分泌的干扰素-γ和肿瘤坏死因子-α减少。此外，过量的IL-6抑制细胞因子的产生和CD8+T细胞的增殖。最后,IL-6水平高的参与者表现出非T细胞炎症的免疫抑制肿瘤微环境.
UASSIGNED：在Ate/Bev治疗后，高基线IL-6水平可能与不良临床结局和T细胞功能受损相关。
UNASSIGNED：尽管对阿特珠单抗和贝伐单抗治疗有反应的肝细胞癌患者表现出良好的临床结局，其中一小部分仍然存在主要阻力。我们发现，在接受阿特珠单抗和贝伐单抗治疗的肝细胞癌患者中，高基线血清IL-6水平与不良临床结果和T细胞反应受损相关。
