Higher Expression of Ku80 and Ku70 Indicates Hotter Tumor Immune Microenvironment in Hepatocellular Carcinoma and Better CTL-Centered Immunotherapy

Lukun Yang; Ling Li; Peiping Li; Jiafan Chen; Chaonong Cai; Yingbin Jia; Jian Li; Baojia Zou

doi:10.2147/JIR.S496123

Higher Expression of Ku80 and Ku70 Indicates Hotter Tumor Immune Microenvironment in Hepatocellular Carcinoma and Better CTL-Centered Immunotherapy

J Inflamm Res. 2024 Nov 22:17:9511-9525. doi: 10.2147/JIR.S496123. eCollection 2024.

Authors

Lukun Yang^#^{1

2}, Ling Li^#³, Peiping Li^#¹, Jiafan Chen¹, Chaonong Cai¹, Yingbin Jia¹, Jian Li¹, Baojia Zou¹

Affiliations

¹ Department of Hepatobiliary Surgery, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong Province, People's Republic of China.
² Department of Anesthesiology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, Guangdong Province, People's Republic of China.
³ Department of Pharmacy, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Both Ku80 and Ku70 are promising drug targets for hepatocellular carcinoma (HCC) and crucial for immune regulation. However, their correlation with HCC immune signatures has not yet been investigated. Therefore, we aimed to investigate the relationship between Ku80, Ku70, and immune signatures in HCC and validate their significance in cytotoxic lymphocyte (CTL) immunotherapy.

Patients and methods: Analyses of Ku70, Ku80, and immune signatures in public datasets was performed using R software, an online Kaplan-Meier plotter, g:Profiler, GeneTrail, and Metascape. Uniform manifold approximation and projection, correlation chord diagrams, Pearson's correlation tests, and Spearman correlation tests were used to describe various correlation levels. HCC mRNA sequencing data (n=373 tumor samples and n=50 para-tumor samples) were drawn from The Cancer Genome Atlas (TCGA) public database. Immunofluorescent staining was used to validate Ku70/Ku80 and CD8⁺CTL expression in 120 HCC patients from our center. Survival analysis was performed using the Kaplan-Meier survival analysis with the Log rank test and was adopted to analyze immunotherapy outcomes correlated with Ku70/Ku80 expression in various solid tumors. Multivariate analysis of HCC patient data from our center was performed using a Cox proportional hazards model.

Results: Increased Ku70/Ku80 expression positively correlated with more enriched immune microenvironment signatures, indicating increased immune infiltration in HCC. Upregulation of Ku70/Ku80 indicated better anti-PD1 and anti-PDL1 treatment outcomes in various solid tumors. Higher Ku70/Ku80 expression with lower CD8⁺CTL signatures indicated worse survival outcomes, whereas lower Ku70/Ku80 expression with higher CD8⁺CTL signatures indicated the best prognosis.

Conclusion: Higher Ku70/Ku80 expression indicated an immune-hot infiltration signature in HCC. Patients with increased Ku70/Ku80 expression and high CD8⁺CTL signatures may potentially benefit from CTL-centered immunotherapies.

Keywords: CTL-centered immunotherapy; XRCC5/Ku80; XRCC6/Ku70; hepatocellular carcinoma; tumor immune microenvironment.

Grants and funding

This work was funded by the National Natural Science Foundation of China (grant number 82272105), Guangdong Basic and Applied Basic Research Foundation (grant number 2020A1515010203, 2022A1515011244, 2022A1515012382, 2023A1515011521, 2023A1515010475), Medical Scientific Research Foundation of Guangdong Province of China (A2017421, 2016116212141586).