Identification of an Immune-Related Risk Signature Correlates With Immunophenotype and Predicts Anti-PD-L1 Efficacy of Urothelial Cancer.

Pengju Li,Junhang Luo,Jiaying Li,Mingxiao Zhang,Chengpeng Gui,Jiazheng Cao,Jinhuan Wei,Yong Huang,Yongkang Ye,Yiming Tang,Lei Tan,Zhuangyao Liao,Wei Chen,Xu Chen,Jiefei Xiao,Shihui Hao

doi:10.3389/fcell.2021.646982

Abstract

Immune checkpoint inhibitor (ICI) treatment has been used to treat advanced urothelial cancer. Molecular markers might improve risk stratification and prediction of ICI benefit for urothelial cancer patients. We analyzed 406 cases of bladder urothelial cancer from The Cancer Genome Atlas (TCGA) data set and identified 161 messenger RNAs (mRNAs) as differentially expressed immunity genes (DEIGs). Using the LASSO Cox regression model, an eight-mRNA-based risk signature was built. We validated the prognostic and predictive accuracy of this immune-related risk signature in 348 metastatic urothelial cancer (mUC) samples treated with anti-PD-L1 (atezolizumab) from IMvigor210. We built an immune-related risk signature based on the eight mRNAs: ANXA1, IL22, IL9R, KLRK1, LRP1, NRG3, SEMA6D, and STAP2. The eight-mRNA-based risk signature successfully categorizes patients into high-risk and low-risk groups. Overall survival was significantly different between these groups, regardless if the initial TCGA training set, the internal TCGA testing set, all TCGA set, or the ICI treatment set. The hazard ratio (HR) of the high-risk group to the low-risk group was 3.65 (p < 0.0001), 2.56 (p < 0.0001), 3.36 (p < 0.0001), and 2.42 (p = 0.0009). The risk signature was an independent prognostic factor for prediction survival. Moreover, the risk signature was related to immunity characteristics. In different tumor mutational burden (TMB) subgroups, it successfully categorizes patients into high-risk and low-risk groups, with significant differences of clinical outcome. Our eight-mRNA-based risk signature is a stable biomarker for urothelial cancer and might be able to predict which patients benefit from ICI treatment. It might play a role in precision individualized immunotherapy.

Highlights

Bladder cancer is a common tumor of the urinary system; 90% of the pathological types are urothelial cancer (UC)
After preliminary screening through single-factor regression analysis and difference analysis based on immunity clustering, a total of 1,976 genes were identified as differentially expressed genes (DEGs)
161 genes were identified as differentially expressed immunity genes (DEIGs) based on ImmPort and InnateDB databases (Figure 2C)

Summary

Introduction

Bladder cancer is a common tumor of the urinary system; 90% of the pathological types are urothelial cancer (UC). For bladder cancer patients with local progression or distant metastasis, cisplatin combined with gemcitabine is the first choice. The median survival time of patients is only 15 months, and the 5 years survival rate is difficult to reach 15% (Griffiths et al, 2011). With the rapid development of tumor immune checkpoint inhibitors (ICIs), especially the rapid development of programmed cell death molecule 1 (PD-1)/programmed cell death molecule ligand 1 (PD-L1) inhibitors, the treatment of bladder cancer patients has brought new options. In patients with metastatic UC (mUC) who cannot receive cisplatin chemotherapy and PDL1 positive, ICIs can already be used as a first-line treatment (Nadal and Bellmunt, 2019)

Methods

Results

Conclusion