Background: Reversal of CD8 T-cell exhaustion was considered a major antitumor mechanism of anti-programmed cell death-1 (PD-1)/ anti-programmed death ligand-1 (PD-L1)-based immune checkpoint inhibitor (ICI) therapy. Objectives: The aim of this study was to identify markers of T-cell exhaustion that is best associated with ICI treatment efficacy for advanced hepatocellular carcinoma (HCC). Methods: Immune cell composition of archival tumor samples was analyzed by transcriptomic analysis and multiplex immunofluorescence staining. Results: HCC patients with objective response after anti-PD-1/anti-PD-L1-based ICI therapy (n = 42) had higher expression of genes related to T-cell exhaustion. A 9-gene signature (LAG3, CD244, CCL5, CXCL9, CXCL13, MSR1, CSF3R, CYBB, and KLRK1) was defined, whose expression was higher in patients with response to ICI therapy, correlated with density of CD8⁺LAG3⁺ cells in tumor microenvironment, and independently predicted better progression-free and overall survival. This 9-gene signature had similar predictive values for patients who received single-agent or combination ICI therapy and was not associated with prognosis in HCC patients who received surgery, suggesting that it may outperform other T-cell signatures for predicting efficacy of ICI therapy for HCC. For HCC patients who underwent surgery for both the primary liver and metastatic lung tumors (n = 31), lung metastatic HCC was associated with a higher exhausted CD8 T-cell signature, consistent with prior observation that patients with lung metastatic HCC may have higher probability of response to ICI therapy. Conclusions: CD8 T-cell exhaustion in tumor microenvironment may predict better efficacy of ICI therapy for HCC.
Liver Cancer

中文翻译：

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探索耗竭 CD8 T 细胞的标志物以预测对肝细胞癌免疫检查点抑制剂治疗的反应

背景：逆转 CD8 T 细胞耗竭被认为是基于抗程序性细胞死亡 1 (PD-1)/抗程序性死亡配体 1 (PD-L1) 的免疫检查点抑制剂 (ICI) 治疗的主要抗肿瘤机制. 目的：本研究的目的是确定与晚期肝细胞癌 (HCC) 的 ICI 治疗效果最相关的 T 细胞衰竭标志物。方法：通过转录组分析和多重免疫荧光染色分析存档肿瘤样本的免疫细胞组成。结果：基于抗 PD-1/抗 PD-L1 的 ICI 治疗后有客观反应的 HCC 患者（ n= 42) 与 T 细胞衰竭相关的基因表达较高。定义了一个 9 基因特征（LAG3、CD244、CCL5、CXCL9、CXCL13、MSR1、CSF3R、CYBB 和 KLRK1），其表达在对 ICI 治疗有反应的患者中更高，与 CD8 ⁺ LAG3 ⁺细胞的密度相关肿瘤微环境，并独立预测更好的无进展生存期和总生存期。这种 9 基因特征对接受单药或联合 ICI 治疗的患者具有相似的预测值，并且与接受手术的 HCC 患者的预后无关，这表明它在预测 ICI 治疗疗效方面可能优于其他 T 细胞特征。肝癌。对于同时接受原发性肝脏和转移性肺肿瘤手术的 HCC 患者（n= 31)，肺转移性 HCC 与更高的耗竭 CD8 T 细胞特征相关，这与之前的观察一致，即肺转移性 HCC 患者可能对 ICI 治疗有更高的反应概率。结论：肿瘤微环境中 CD8 T 细胞耗竭可预测 ICI 治疗 HCC 的更好疗效。
肝癌