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

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.

Integrated bioinformatics analysis and experimental validation reveals fatty acid metabolism-related prognostic signature and immune responses for uterine corpus endometrial carcinoma

“…The results showed that patients with higher TMB possessed a better prognosis than those with lower TMB. Similar findings have been observed in other cancers (40)(41)(42), highlighting the possibility that TMB might serve as a prognostic marker for guiding more efficient immunotherapeutic approaches (43). By combing with FAMGs risk score, patients with low-TMB/ high-FAMGs had the lowest survival probability than other groups.…”

Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy

“…Additionally, TAMs are associated with tumor recurrence in NMIBC patients [ 42 , 43 ]. In both NMIBC and MIBC patients, a high number of TAMs is associated with a higher risk of tumor progression [ 31 , 44 ], as well as a worse progression-free survival (PFS) and overall survival (OS) [ 27 , 29 , 35 , 45 ]. Depending on the phenotype and localization, macrophages can be associated with opposite clinical outcomes in BCa.…”

Scoring System Based on RNA Modification Writer-Related Genes to Predict Overall Survival and Therapeutic Response in Bladder Cancer

“…Some clinical parameters, including PD-L1 expression (47), CD8+ T cells (48), TMB (32), and microsatellite instability (MSI) (49), are used to predict immunotherapy treatment efficacy. It has also been reported that an immune-associated gene signature correlates with the immunophenotype, which could predict the anti-PD-L1 effect of urothelial cancer (50). While all of these factors or signatures were based on indicators associated with the immune response, our findings suggested that RNA modification patterns could also possess potential biological functions in predicting the efficacy of immunotherapy.…”