Development of a novel gene signature to predict prognosis and response to PD-1 blockade in clear cell renal cell carcinoma

• Published in: Oncoimmunology Vol. 10; no. 1; p. 1933332
• Main Authors: Yin, Xiaomao, Wang, Zaoyu, Wang, Jianfeng, Xu, Yunze, Kong, Wen, Zhang, Jin
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.01.2021; Taylor & Francis Group
• Subjects: Biomarkers, Tumor - genetics; Carcinoma, Renal Cell - drug therapy; Clear cell renal cell carcinoma; Gene Expression Regulation, Neoplastic; gene signature; Humans; Immune Checkpoint Inhibitors; immune infiltration; immunotherapy; Kidney Neoplasms - drug therapy; Original Research; Prognosis; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - genetics; tissue microarray; Tumor Microenvironment; Clear cell renal cell carcinoma; gene signature; immune infiltration; tissue microarray; immunotherapy
• ISSN: 2162-402X; 2162-4011; 2162-402X
• DOI: 10.1080/2162402X.2021.1933332

Clear cell renal cell carcinoma (ccRCC) is the most common kidney malignancy characterized by a poor prognosis. The treatment efficacy of immune checkpoint inhibitors (ICIs) also varies widely in advanced ccRCC. We aim to construct a robust gene signature to improve the prognostic discrimination and prediction of ICIs for ccRCC patients. In this study, adopting differentially expressed genes from seven ccRCC datasets in GEO (Gene Expression Omnibus), a novel signature (FOXM1&TOP2A) was constructed in TCGA (The Cancer Genome Atlas) database by LASSO and Cox regression. Survival and time-dependent ROC analysis revealed the strong predictive ability of our signature in discovery set, two online validation sets and one tissue microarray (TMA) from our institution. High-risk group based on the signature comprises more high-grade (G3&G4) and advanced pathologic stage (stageIII/IV) tumors and presents hyperactivation of cell cycle process according to the functional analysis. Meanwhile, high-risk tumors demonstrate an immunosuppressive phenotype with more infiltrations of regulatory T cells (Tregs), macrophages and high expressions of genes negatively regulating anti-tumor immunity. Low-risk tumors have an improved response to anti-PD-1 therapy and the predictive ability of our signature is better than other recognized biomarkers in ccRCC. A nomogram containing this signature showed a high predictive accuracy with AUCs of 0.90 and 0.84 at 3 and 5 years. Overall, this robust signature could predict prognosis, evaluate immune microenvironment and response to anti-PD-1 therapy in ccRCC, which is very promising in clinical promotion.