An Unfolded Protein Response Related Signature Could Robustly Predict Survival Outcomes and Closely Correlate With Response to Immunotherapy and Chemotherapy in Bladder Cancer

Abstract

Background: The unfolded protein response (UPR) plays a significant role in maintaining protein hemostasis in tumor cells, which are crucial for tumor growth, invasion, and resistance to therapy. This study aimed to develop a UPR-related signature and explore its correlation with immunotherapy and chemotherapy in bladder cancer.Methods: The differentially expressed UPR-related genes were put into Lasso regression to screen out prognostic genes, which constituted the UPR signature, and were incorporated into multivariate Cox regression to generate risk scores. Subsequently, the predictive performance of this signature was estimated by receiver operating characteristic (ROC) curves. The CIBERSORTx, the maftool, and Gene set enrichment analysis (GSEA) were applied to explore infiltrated immune cells, tumor mutational burden (TMB), and enriched signaling pathways in both risk groups, respectively. Moreover, The Cancer Immunome Atlas (TCIA) and Genomics of Drug Sensitivity in Cancer (GDSC) databases were used to predict responses to chemotherapy and immunotherapy.Results: Twelve genes constituted the UPR-related signature. Patients with higher risk scores had worse overall survival (OS) in training and three validation sets. The UPR-related signature was closely correlated with clinicopathologic parameters and could serve as an independent prognostic factor. M0 macrophages showed a significantly infiltrated difference in both risk groups. TMB analysis showed that the risk score in the wild type and mutation type of FGFR3 was significantly different. GSEA indicated that the immune-, extracellular matrix-, replication and repair associated pathways belonged to the high risk group and metabolism-related signal pathways were enriched in the low risk group. Prediction of immunotherapy and chemotherapy revealed that patients in the high risk group might benefit from chemotherapy, but had a worse response to immunotherapy. Finally, we constructed a predictive model with age, stage, and UPR-related risk score, which had a robustly predictive performance and was validated in GEO datasets.Conclusion: We successfully constructed and validated a novel UPR-related signature in bladder cancer, which could robustly predict survival outcomes and closely correlate with the response to immunotherapy and chemotherapy in bladder cancer.

Identification of endothelial-related molecular subtypes for bladder cancer patients

“…The mean TMB score of cluster 1 was substantially higher than that of cluster 2. A high TMB score was positively associated with the immunotherapy response rate, which also supported our hypotheses ( 35 ). Inadequate nutrient supply and hypoxia caused by inadequate nutrient supply and hypoxia promote enrichment of cancer stem cells ( 12 , 36 ).…”

“…Cluster 1 had a statistically higher mRNAsi score than cluster 2, which also supported that patients in the cluster 1 were more likely to benefit from immunotherapy. Given the results of TMB and mRNAsi, patients with high microsatellite instability (MSI) scores could benefit more from immunotherapy ( 35 ). The comparison results of the MSI Expr Sig score between the clusters supported that patients in the cluster 1 were more likely to benefit from immunotherapy.…”

Prognostic nomogram based on the lymph node metastasis indicators for patients with bladder cancer: A SEER population‐based study and external validation

“…The analysis of immune cell infiltration suggested that the high‐risk group had a higher infiltration of M0 macrophages and plasma cells, while T follicular helper cells were more abundant in low‐risk group. The high proportion of M0 macrophages, indicating a higher level of inflammatory activation, was correlated with poor prognosis of BC patients 46,47 . It has previously been reported that more recruitment of naïve M0 macrophages is associated with early LNM, which could prevent T cells from attacking tumor cells and secrete growth factors promoting tumor angiogenesis 48,49 .…”

“…The high proportion of M0 macrophages, indicating a higher level of inflammatory activation, was correlated with poor prognosis of BC patients. 46 , 47 It has previously been reported that more recruitment of naïve M0 macrophages is associated with early LNM, which could prevent T cells from attacking tumor cells and secrete growth factors promoting tumor angiogenesis. 48 , 49 T follicular helper cells might contribute to the maintenance of a protective immune response, which was proved to be associated with better prognosis in BC.…”

Unfolded Protein Response–Related Signature Associates With the Immune Microenvironment and Prognostic Prediction in Osteosarcoma

“…The mRNA expression profiles and corresponding clinical features of 85 osteosarcoma patients were acquired from the TARGET database as a training cohort ( https://ocg.cancer.gov/ programs/target). UPRRGs were extracted from hallmark gene sets from the Molecular Signature Database ( Zhang et al, 2021 ). In addition, mRNA expression profiles and relevant clinical information of 53 osteosarcoma patients from GSE21257 were obtained from the GEO database to serve as an external validation cohort ( https://www.ncbi.nlm.nih.gov/geo/ ).…”