Machine Learning-based Development and Validation of a Cell Senescence Predictive and Prognostic Signature in...

Background: Previous studies have shown that cellular senescence is strongly associated with tumorigenesis and the tumor microenvironment. Accordingly, we developed a novel prognostic signature for intrahepatic cholangiocarcinoma (ICCA) based on senescence-associated long non-coding RNAs (SR-lncRNAs) and identified a lncRNA-miRNA-mRNA axis involving in ICCA. Methods: Based on the 197 senescence-associated genes (SRGs) from Genacards and their expression in Fu-ICCA cohort, we identified 20 lncRNAs as senescence-associated lncRNAs (SR-lncRNAs) through co-expression and cox-regression analysis. According to 20 SR-lncRNAs, patients with ICCA were classified into 2 molecular subtypes using unsupervised clustering machine learning approach and to explore the prognostic and functional heterogeneity between these two subtypes. Subsequently, we integrated 113 machine learning algorithms to develop senescence-related lncRNA signature, ultimately identifying 11 lncRNAs and constructing prognostic models and risk stratification. The correlation between the signature and the immune landscape, immunotherapy response as well as drug sensitivity are explored too. Results: We developed a novel senescence related signature. The predictive model and risk score calculated by the signature exhibited favorable prognostic predictive performance, which is a suitable independent risk factor for the prognosis of patients with ICCA based on Kaplan-Meier plotter, nomogram and receiving operating characteristic (ROC) curves. The results were validated using external datasets. Estimate, ssGSEA (single sample gene set enrichment analysis), IPS (immunophenotype score) and TIDE (tumor immune dysfunction and exclusion) algorithms revealed higher immune infiltration, higher immune scores, lower immune escape potential and better response to immunotherapy in the high-risk group. In addition, signature identifies eight chemotherapeutic agents, including cisplatin for patients with different risk levels, providing guidance for clinical treatment. Finally, we identified a set of lncRNA-miRNA-mRNA axes involved in ICCA through regulation of senescence. Conclusion: SR-lncRNAs signature can favorably predict the prognosis, risk stratification, immune landscape and immunotherapy response of patients with ICCA and consequently guide individualized treatment.