AUTHOR=Luo Yi , Liu Hao , Fu Hong , Ding Guo-Shan , Teng Fei 

TITLE=A cellular senescence-related classifier based on a tumorigenesis- and immune infiltration-guided strategy can predict prognosis, immunotherapy response, and candidate drugs in hepatocellular carcinoma

JOURNAL=Frontiers in Immunology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.974377

DOI=10.3389/fimmu.2022.974377

ISSN=1664-3224

ABSTRACT=ABSTRACT
Background: Cellular senescence plays an irreplaceable role in tumorigenesis, progression, and tumor microenvironment (TME) remodeling. However, to date, there are limited researches delineating the landscape of cellular senescence in hepatocellular carcinoma (HCC), and an improved understanding on the interaction of tumor-associated cellular senescence with HCC prognosis, TME, and response to immunotherapy is warrant.
Methods: Tumorigenic and immune infiltration-associated senescence genes were determined by weighted gene co-expression network analysis (WGCNA) and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) algorithm, and subsequently, a prognostic scoring model (named TIS) was constructed using multiple survival analysis algorithms to classify the senescence-related subtypes of HCC. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) were conducted to identify the distinct hallmark pathways between high- and low-risk subtypes. Additionally, we carried out correlation analyses for TIS and clinical traits, senescence-associated secretory phenotype (SASP), immune infiltration and evasion, immune checkpoint factors, drug response, and immunotherapeutic efficacy.   
Results: A 5-gene TIS, composed of NET, ATP6V0B, MMP1, GTDC1 and CPEB3, was constructed and validated using TCGA and ICGC datasets, respectively, and showed a highly robust and plausible signature for overall survival (OS) prediction of HCC both in training and validation cohort. Patients in TIS-high group were accompanied with worse OS, activation of carcinogenetic pathways, infiltration of immunosuppressive cells, exclusion of effector killing cells, overexpression of immunomodulatory genes and SASP, and unsatisfied response to immunotherapy. In response to anti-cancer drugs, patients in TIS-high group exhibited enhanced susceptibility to several conventional chemotherapeutic agents (5-fluorouracil, docetaxel, doxorubicin, gemcitabine, and etoposide), as well as several inhibitors of pathways involving in cellular senescence (cell-cycle inhibitors, bromodomain and extraterminal domain family (BET) inhibitors, PI3K-AKT pathway inhibitors, and multikinase inhibitors). Additionally, four putative drugs (palbociclib, JAK3 inhibitor VI, floxuridine, and lestaurtinib) were identified as potential compounds for patients in TIS-high group.
Conclusions: Our study provides comprehensive clues demonstrating the role of novel TIS in predicting HCC prognosis, immunotherapeutic response, and candidate drugs. This work highlights the significance of tumorigenesis- and immune infiltration-related cellular senescence in cancer therapy.
Keywords: Cellular senescence; Hepatocellular carcinoma; Tumor microenvironment; Prognosis; Immunotherapy