Table1_ASF1B is a Promising Prognostic Biomarker and Correlates With Immunotherapy Efficacy in Hepatocellular Carcinoma.DOC

Background: Anti-silencing function 1B (ASF1B), a histone H3-H4 chaperone, is crucial for S-phase progression and cell proliferation. Recent studies have shown that ASF1B may be used as a new proliferation marker for cancer prognosis. However, the prognostic value and effect of ASF1B on tumor cells and the immune microenvironment in hepatocellular carcinoma (HCC) remain unclear.
Methods: We analyzed the expression of ASF1B and its prognostic value using The Cancer Genome Atlas (TCGA) database (as a training set) and other databases, and we validated the findings by immunohistochemistry in our clinical database, containing 141 HCC patients (as a validation set). Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were performed to probe the tumor-associated biological processes of ASF1B in HCC. The interrelationships between ASF1B expression and tumor immunological characteristics were analyzed by multiple databases. The Imvigor210 cohort was retrieved to assess the ability of ASF1B to predict immunotherapy efficacy.
Results: ASF1B was highly expressed in tumor tissue compared to paracancerous tissue. High ASF1B expression was associated with worse overall survival (OS) and progression-free survival (PFS) in the training set (p = 0.005, p < 0.001) and validation set (p < 0.001, p < 0.001). Multivariate analysis revealed that ASF1B was an independent prognostic factor associated with OS and PFS. GSEA and GSVA suggested that ASF1B was involved in tumor-associated biological processes, including the cell cycle, DNA replication, base excision repair, mismatch repair, RNA degradation, ubiquitin-mediated proteolysis, and nucleotide excision repair. Further analysis revealed that the levels of ASF1B were positively correlated with the immune cells infiltration of B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells. However, ASF1B was positively correlated with Treg cell infiltration and inhibitory immune checkpoints in exhausted T cells. Patients who received anti-PD-L1 immunotherapy with high ASF1B expression had a higher objective response.
Conclusion: The ASF1B level is an independent prognostic factor and may serve as a potential immunotherapeutic target.

背景：抗沉默功能1B（Anti-silencing function 1B, ASF1B）是一种组蛋白H3-H4伴侣蛋白，对S期进程与细胞增殖至关重要。近年研究表明，ASF1B可作为癌症预后的新型增殖标志物。然而，ASF1B在肝细胞癌（hepatocellular carcinoma, HCC）中的预后价值、对肿瘤细胞及免疫微环境的影响仍未明确。
方法：本研究借助癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库（作为训练集）及其他数据库分析ASF1B的表达水平及其预后价值，并通过免疫组化（immunohistochemistry）在包含141例HCC患者的临床队列（作为验证集）中验证了研究结果。采用基因集富集分析（gene set enrichment analysis, GSEA）与基因集变异分析（gene set variation analysis, GSVA）探究ASF1B在HCC中相关的肿瘤生物学过程。通过多数据库分析ASF1B表达与肿瘤免疫特征之间的关联。检索Imvigor210队列以评估ASF1B预测免疫治疗疗效的能力。
结果：相较于癌旁组织，ASF1B在肿瘤组织中呈高表达。在训练集与验证集中，ASF1B高表达均与较差的总生存期（overall survival, OS）及无进展生存期（progression-free survival, PFS）相关（训练集：p=0.005，p<0.001；验证集：p<0.001，p<0.001）。多因素分析显示，ASF1B是与OS及PFS相关的独立预后因素。GSEA与GSVA结果表明，ASF1B参与诸多肿瘤相关生物学过程，包括细胞周期、DNA复制、碱基切除修复、错配修复、RNA降解、泛素介导的蛋白水解及核苷酸切除修复。进一步分析显示，ASF1B表达水平与B细胞、CD8+T细胞、CD4+T细胞、中性粒细胞及树突状细胞的浸润程度呈正相关。但ASF1B表达与调节性T细胞（regulatory T cell, Treg）浸润及耗竭T细胞的抑制性免疫检查点呈正相关。接受抗PD-L1免疫治疗且ASF1B高表达的患者，其客观缓解率更高。
结论：ASF1B表达水平是独立预后因素，有望成为潜在的免疫治疗靶点。