ASF1B is a Promising Prognostic Biomarker and Correlates With Immunotherapy Efficacy in Hepatocellular Carcinoma.

Shirong Zhang,Wenyuan Li,Jinteng Feng,Hui Guo,Lili Jiang,Wenjuan Wang,Min Jiao,Yue Zhu,Jia Hou,Longwen Xu,Deli Tan,Kejia Lv

doi:10.3389/fgene.2022.842351

Abstract

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.

Highlights

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is estimated to be the fourth most common cause of cancer-related death, which exacts a heavy disease burden worldwide (Llovet et al, 2021)
Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) suggested that Anti-silencing function 1B (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
Because ASF1B was associated with immune cell infiltration in tumors and positively correlated with immune checkpoint coinhibitory molecules, we further explored the relationship between ASF1B and the efficacy of immunotherapy, and we identified the value of ASF1B as a predictive marker

Summary

Introduction

Hepatocellular carcinoma (HCC), the major type of primary liver cancer, is estimated to be the fourth most common cause of cancer-related death, which exacts a heavy disease burden worldwide (Llovet et al, 2021). Advancements in the clinical management of HCC have improved patient survival, the prognosis of HCC remains poor due to the high rate of frequent recurrence and intrahepatic metastasis. Many studies have demonstrated that immune checkpoint inhibitors (ICIs), including atezolizumab, nivolumab, and pembrolizumab, are revolutionizing cancer therapy in HCC by inducing durable antitumor responses and overall survival benefits (El-Khoueiry et al, 2017; Zhu et al, 2018; Finn et al, 2020; Yau et al, 2020). Only a minority of patients achieve this transcendent, durable benefit from ICIs. identifying a biomarker to predict prognosis and response to ICIs for HCC treatment is urgently required. Recent studies have shown that ASF1B may be used as a new proliferation marker for cancer prognosis. The prognostic value and effect of ASF1B on tumor cells and the immune microenvironment in hepatocellular carcinoma (HCC) remain unclear

Methods

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Discussion

Conclusion