Identifying tumor immunity-associated molecular features in liver hepatocellular carcinoma by multi-omics analysis

Abstract

Background: Although current immunotherapies have achieved some successes for hepatocellular carcinoma (HCC) patients, their benefits are limited for most HCC patients. Therefore, the identification of biomarkers for promoting immunotherapeutic responses in HCC is urgently needed.Methods: Using the TCGA HCC cohort, we investigated correlations of various molecular features with antitumor immune signatures (CD8+ T cell infiltration and cytolytic activity) and an immunosuppressive signature (PD-L1 expression) in HCC. These molecular features included mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and pathways.Results: We found that the mutations of several oncogenes and tumor suppressor genes significantly correlated with reduced antitumor immune signatures, including TTN, CTNNB1, RB1, ZFHX4, and TP53. It indicates that these genes’ mutations may inhibit antitumor immune responses in HCC. Four proteins (Syk, Lck, STAT5, and Caspase-7) had significant positive expression correlations with CD8+ T cell enrichment, cytolytic activity, and PD-L1 expression in HCC. It suggests that these proteins’ expression could be useful biomarkers for the response to immune checkpoint inhibitors Similiarly, we identified other types of biomarkers potentially useful for predicting the response to ICIs, including miRNAs (hsa-miR-511-5p, 150-3p, 342-3p, 181a-3p, 625-5p, 4772-3p, 155-3p, 142-5p, 142-3p, 155-5p, 625-3p, 1976, 7702), many lncRNAs, and pathways (apoptosis, cytokine-cytokine receptor interaction, Jak-STAT signaling, MAPK signaling, PI3K-AKT signaling, HIF-1 signaling, ECM receptor interaction, focal adhesion, and estrogen signaling). Further, tumor mutation burden showed no significant correlation with antitumor immunity, while tumor aneuploidy levels showed a significant negative correlation with antitumor immunity.Conclusion: The molecular features significantly associated with HCC immunity could be predictive biomarkers for immunotherapeutic responses in HCC patients. They could also be potential intervention targets for boosting antitumor immunity and immunotherapeutic responses in HCC.

Identification of oncogenes and tumor-suppressor genes with hepatocellular carcinoma: A comprehensive analysis based on TCGA and GEO datasets

“…There is an urgent need to find new targets for the diagnosis and treatment of liver cancer in the direction of a breakthrough in the current treatment limitations. Some previous studies used TCGA and GEO databases to screen oncogenes and identify prognostic or immune-related genes ( Chen et al, 2020 ; Gao et al, 2021 ; Yan et al, 2021 ; Shen et al, 2022a ; Shen et al, 2022b ; Ding et al, 2022 ; Gao et al, 2022 ; Long et al, 2022 ; Yang et al, 2022 ). However, in this study, four GSE datasets, GSE36376, GSE102079, GSE54236, and GSE45267, were summarized for analysis, hoping to find the mechanism of cancer-promoting and tumor-suppressor factors in liver cancer from the perspective of improving the accuracy of the research results.…”

“…Currently, public data and bioinformatic analysis methods have provided us with invaluable resources to find HCC-related oncogenes and tumor-suppressor genes. Some studies searched cancer-related target genes through public databases, whether prognostic oncogene identification ( Gao et al, 2021 ; Yan et al, 2021 ; Shen et al, 2022a ; Gao et al, 2022 ), single-gene research studies ( Ding et al, 2022 ; Yang et al, 2022 ), or immune-related oncogenes ( Chen et al, 2020 ; Shen et al, 2022b ; Long et al, 2022 ), all of which provided a strong basis for targeted therapy and precise treatment of liver cancer. However, many studies only consider the differential expression of oncogenes in tumors, ignoring the important role and potential association of tumor-suppressor genes.…”