A reactive oxygen species-related signature to predict prognosis and aid immunotherapy in clear cell renal cell carcinoma

Hongxiang Liu; Yong Luo; Shankun Zhao; Jing Tan; Minjian Chen; Xihai Liu; Jianheng Ye; Shanghua Cai; Yulin Deng; Jinchuang Li; Huichan He; Xin Zhang; Weide Zhong

doi:10.3389/fonc.2023.1202151

A reactive oxygen species-related signature to predict prognosis and aid immunotherapy in clear cell renal cell carcinoma

Front Oncol. 2023 Jul 11:13:1202151. doi: 10.3389/fonc.2023.1202151. eCollection 2023.

Authors

Hongxiang Liu^{1

2}, Yong Luo³, Shankun Zhao⁴, Jing Tan⁵, Minjian Chen², Xihai Liu², Jianheng Ye⁶, Shanghua Cai^{7

8}, Yulin Deng⁷, Jinchuang Li⁶, Huichan He⁸, Xin Zhang⁹, Weide Zhong^{1

6

7

8

10}

Affiliations

¹ School of Medicine, Jinan University, Guangzhou, China.
² Department of Urology, The First People's Hospital of Zhaoqing, Zhaoqing, China.
³ Department of Urology, The Second People's Hospital of Foshan, Affiliated Foshan Hospital of Southern Medical University, Foshan, China.
⁴ Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China.
⁵ Department of Pediatrics, The First People's Hospital of Zhaoqing, Zhaoqing, China.
⁶ Department of Urology, Guangdong Key Laboratory of Clinical Molecular Medicine and Diagnostics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.
⁷ Urology Key Laboratory of Guangdong Province, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
⁸ Guangzhou Medical University, Guangzhou Laboratory, Guangzhou, China.
⁹ Department of Pathology, The Second People's Hospital of Foshan, Affiliated Foshan Hospital of Southern Medical University, Foshan, China.
¹⁰ Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, Macao SAR, China.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is a malignant disease containing tumor-infiltrating lymphocytes. Reactive oxygen species (ROS) are present in the tumor microenvironment and are strongly associated with cancer development. Nevertheless, the role of ROS-related genes in ccRCC remains unclear.

Methods: We describe the expression patterns of ROS-related genes in ccRCC from The Cancer Genome Atlas and their alterations in genetics and transcription. An ROS-related gene signature was constructed and verified in three datasets and immunohistochemical staining (IHC) analysis. The immune characteristics of the two risk groups divided by the signature were clarified. The sensitivity to immunotherapy and targeted therapy was investigated.

Results: Our signature was constructed on the basis of glutamate-cysteine ligase modifier subunit (GCLM), interaction protein for cytohesin exchange factors 1 (ICEF1), methionine sulfoxide reductase A (MsrA), and strawberry notch homolog 2 (SBNO2) genes. More importantly, protein expression levels of GCLM, MsrA, and SBNO2 were detected by IHC in our own ccRCC samples. The high-risk group of patients with ccRCC suffered lower overall survival rates. As an independent predictor of prognosis, our signature exhibited a strong association with clinicopathological features. An accurate nomogram for improving the clinical applicability of our signature was constructed. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that the signature was closely related to immune response, immune activation, and immune pathways. The comprehensive results revealed that the high-risk group was associated with high infiltration of regulatory T cells and CD8+ T cells and more benefited from targeted therapy. In addition, immunotherapy had better therapeutic effects in the high-risk group.

Conclusion: Our signature paved the way for assessing prognosis and developing more effective strategies of immunotherapy and targeted therapy in ccRCC.

Keywords: clear cell renal cell carcinoma; immune infiltrates; immunotherapy; prognosis; reactive oxygen species.

Grants and funding

This study was supported by the National Natural Science Foundation of China (82072813), the Science and Technology Development Fund (FDCT) of Macau SAR (0031/2021/A and 0090/2022/A), and The Second People’s Hospital of Foshan Fund Project (2022B05).