Analysis of the potential association between ferroptosis and immune in hepatocellular carcinoma and their relationship with prognosis

Kai Wen; Feng Yang; Lei Hu; Juanyi Shi; Sintim Mui; Weidong Wang; Hao Liao; Huoming Li; Zhiyu Xiao; Yongcong Yan

doi:10.3389/fonc.2022.1031156

Analysis of the potential association between ferroptosis and immune in hepatocellular carcinoma and their relationship with prognosis

Front Oncol. 2023 Jan 12:12:1031156. doi: 10.3389/fonc.2022.1031156. eCollection 2022.

Authors

Kai Wen¹, Feng Yang², Lei Hu³, Juanyi Shi¹, Sintim Mui¹, Weidong Wang¹, Hao Liao¹, Huoming Li¹, Zhiyu Xiao¹, Yongcong Yan¹

Affiliations

¹ Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
² Department of General Surgery, Affiliated Dongguan Hospital, Southern Medical University (Dongguan People's Hospital), Dongguan, China.
³ Department of Pathology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China.

Abstract

Background: The development of targeted therapy and immunotherapy has enriched the treatment of hepatocellular carcinoma (HCC), however, have had poor or no reponse, or even no response. Previous research suggested that ferroptosis and tumor immune microenvironment (TIME) may have a fundamental impact on efficacy during HCC immunotherapy and targeted therapy. Therefore, there is a clinical need to develop a signature that categorizes HCC patients in order to make more accurate clinical decisions.

Methods: Clinical data and gene expression data of HCC patients were obtained from The Cancer Genome Atlas (TCGA) portal and International Cancer Genome Consortium (ICGC) portal. To identify ferroptosis-related immune-related genes (ferroptosis-related IRGs), Pearson correlation analysis was conducted. The ferroptosis-related IRGs prognostic signature (FIPS) was constructed using Univariate Cox and LASSO Cox algorithms. The predictive effectiveness of FIPS was evaluated using Receiver Operating Characteristic (ROC) curves and survivorship curve. The correlation ship between FIPS and TIME was evaluated using single-sample Gene Set Enrichment Analysis (ssGSEA) and CIBERSORT. The relationship between FIPS and immunotherapy responsiveness was evaluated using immunophenoscore. The expression level of 10 ferroptosis-related IRGs in normal liver tissues and HCC tissues was compared using immunohistochemistry. Finally, we established a nomogram (based on FIPS, TNM stage, and age) for clinical application.

Results: The FIPS was established with ten ferroptosis-related IRGs. The high-FIPS subgroup showed a poor clinical prognosis and an obviously higher proportion of HCC patients with advanced TNM stage, high WHO grade and high alpha fetoprotein(AFP) value. Analysis of TIME indicated that patients in the high-FIPS subgroup may be in immunosuppressed state. Meanwhile, we found that ferroptosis may be inhibited in the high-FIPS subgroup and this subgroup may be impervious to immunotherapy and sorafenib.

Conclusion: We constructed a novel potential prognostic signature for HCC patients that predicts overall survival, ferroptosis and immune status, sorafenib sensitivity, and immunotherapy responsiveness.

Keywords: ferroptosis; gene signature; hepatocellular carcinoma; immune; immunotherapy; sorafenib.

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 82103090, 82073045); Project funded by China Postdoctoral Science Foundation (2020TQ0384, 2021M703742); Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515012391, 2021A1515012107, 2020A1515010232); Science and Technology Program of Guangzhou (No. 202201020311); Medjaden Research Grants for Young Scientists (No. MJR20220907).