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Updated: Jul 9, 2025
Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
Published on: February 8, 2018
PBRM1 mutation and WDR72 expression as potential combinatorial biomarker for predicting the response to Nivolumab in
Qinzheng Chang1, Jiajia Sun1, Shuo Zhao1
1Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong, China.
Purpose:
Immune checkpoint therapy (ICT) provides a new idea for the treatment of advanced clear cell renal cell carcinoma (ccRCC), which can bring significant benefits to patients. However, the clinical application of ICT is limited because of the lack of predictive biomarkers to select potential responders. This study aims to propose a new biomarker to predict the response to Nivolumab in patients with ccRCC.
Materials And Methods:
The genes that significantly improve the prognosis of ccRCC were retrieved from The Cancer Genome Atlas (TCGA) database. The genomic and clinical data were from patients that had been registered in prospective clinical trials (CheckMate 009, CheckMate 010 and CheckMate 025). TCGA, Gene Expression Omnibus (GEO), and The Human Protein Atlas database were used to analyze the gene and protein expression of WD repeat-containing protein 72 (WDR72) in ccRCC. Gene Ontology (GO) & The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were performed to dig relevant mechanisms of WDR72. Single sample gene set enrichment analysis (ssGSEA) was conducted to evaluate the role of WDR72 in immune infiltration. Cell proliferation assay, FAO and ATP quantification were used to explore and verify the molecular mechanisms. The expression of WDR72, FOXP3, CD8, and CPT1A was examined by IHC in 20 advanced ccRCC tissue samples at the Urology Department of our hospital. The MethSurv was used to identify PBRM1 and WDR72 gene methylation and its effect on prognosis of ccRCC.
Results:
WDR72 is the most significant gene for improving overall survival (OS) in ccRCC. In all three checkmates, OS and progression free survival (PFS) were found to be significantly higher in WDR72 high expression group than that in WDR72 low expression group (P=0.040 and P=0.012, respectively), and similar conclusions could be drawn from the PBRM1-mutation (MUT) compared with the PBRM1-wildtype (WT) (P=0.007 and P=0.006, respectively). What's more, high expression of WDR72 plus PBRM1-MUT as a combinatorial biomarker showed improved OS (HR=0.388, P=0.0026) and PFS (HR=0.39, P=0.0066) compared to low expression of WDR72 plus PBRM1-WT. Functional enrichment analysis showed that WDR72 was closely positively related to fatty acid degradation and fatty acid beta oxidation pathway in ccRCC. In vitro experiments showed that high expression of WDR72 can promote fatty acids oxidation and inhibit the proliferation of ccRCC cells. Immune analysis revealed that WDR72 high expression was associated with decreased infiltration of Treg cells and low ssGSEA score of check-point. IHC results showed that WDR72 was negatively correlated with FOXP3 expression (r=-0.506, P=0.023) and positively correlated with CPT1A expression (r=0.529, P=0.017).
Conclusions:
The present study indicated that high expression of WDR72 may indicate a good prognosis of patients treated with Nivolumab and WDR72 expression combined with PBRM1 mutation could be more persuasive to predict the response for ICT in ccRCC patients.
Insights
WD repeat-containing protein 72 (WDR72) is a promising biomarker for predicting response to immune checkpoint therapy (ICT) in advanced clear cell renal cell carcinoma (ccRCC). High WDR72 expression, especially combined with PBRM1 mutation, indicates better survival outcomes for ccRCC patients receiving Nivolumab.
Area of Science:
- Oncology
- Immunotherapy
- Biomarker Discovery
Background:
- Advanced clear cell renal cell carcinoma (ccRCC) treatment benefits from immune checkpoint therapy (ICT).
- Predictive biomarkers are crucial for selecting optimal responders to ICT in ccRCC.
- Current limitations in predictive biomarkers hinder the clinical application of ICT for ccRCC.
Purpose of the Study:
- To identify and propose a novel biomarker for predicting response to Nivolumab in ccRCC patients.
- To investigate the role of WD repeat-containing protein 72 (WDR72) as a predictive biomarker in ccRCC.
Main Methods:
- Retrieved ccRCC prognostic genes from The Cancer Genome Atlas (TCGA) and analyzed clinical trial data (CheckMate 009, 010, 025).
- Assessed WDR72 gene and protein expression using TCGA, Gene Expression Omnibus (GEO), and The Human Protein Atlas.
- Performed Gene Ontology, KEGG, GSEA, ssGSEA, in vitro assays, and immunohistochemistry (IHC) to explore WDR72 mechanisms and correlations.
Main Results:
- High WDR72 expression significantly correlated with improved overall survival (OS) and progression-free survival (PFS) in ccRCC patients treated with Nivolumab.
- Combined WDR72 expression and PBRM1 mutation status served as a powerful combinatorial biomarker, showing superior OS and PFS.
- WDR72 expression was linked to fatty acid degradation pathways, inhibited ccRCC cell proliferation, and correlated with immune cell infiltration markers (FOXP3, CPT1A).
Conclusions:
- High WDR72 expression is a potential indicator of favorable prognosis for ccRCC patients receiving Nivolumab.
- The combination of WDR72 expression and PBRM1 mutation status offers a more persuasive predictive tool for ICT response in ccRCC.
