A Robust Hypoxia Risk Score Predicts the Clinical Outcomes and Tumor Microenvironment Immune Characters in Bladder Cancer

Abstract

BackgroundBladder cancer (BLCA) is one of the most common urinary malignancies with poor prognosis. There is an unmet need to develop novel robust tools to predict prognosis and treatment efficacy for BLCA.MethodsThe hypoxia-related genes were collected from the Molecular Signatures Database. The TCGA-BLCA cohort was downloaded from the Cancer Genome Atlas and then was randomly divided into training and internal validation sets. Two external validation cohorts were gathered from Gene Expression Omnibus. Also, another independent validation cohort (Xiangya cohort) was collected from our hospital. The Cox regression model with the LASSO algorithm was applied to develop the hypoxia risk score. Then, we correlated the hypoxia risk score with the clinical outcomes, the tumor microenvironment (TME) immune characteristics, and the efficacy prediction for several treatments, which included cancer immunotherapy, chemotherapy, radiotherapy, and targeted therapies.ResultsHypoxia risk score was an independent prognostic factor. A high-risk score indicated an inflamed TME based on the evidence that hypoxia risk score positively correlated with the activities of several cancer immunity cycles and the infiltration levels of many tumor-infiltrating immune cells, such as CD8 + T cells, Dendritic cells, and NK cells. Consistently, the hypoxia risk score was positively related to the expression of several immune checkpoints, such as PD-L1, PD-1, CTLA-4, and LAG-3, as well as the T cell inflamed score. Furthermore, the hypoxia risk score positively correlated with the enrichment scores of most immunotherapy-positive gene signatures. Therefore, patients with higher risk score may be more sensitive to cancer immunotherapy. Meanwhile, the hypoxia risk score was positively related to the sensitivities of several chemotherapeutic drugs, including Cisplatin, Docetaxel, Paclitaxel, Bleomycin, Camptothecin, and Vinblastine. Similarly, the enrichment scores for radiotherapy-predicted pathways and EGFR ligands were higher in the high-risk score group. Conversely, the enrichment scores of several immunosuppressive oncogenic pathways were significantly higher in the low-risk score group, such as the WNT-β-catenin network, PPARG network, and FGFR3 network.ConclusionsWe developed and validated a new hypoxia risk score, which could predict the clinical outcomes and the TME immune characteristics of BLCA. In general, the hypoxia risk score may aid in the precision medicine for BLCA.

A Novel TGF-β Risk Score Predicts the Clinical Outcomes and Tumour Microenvironment Phenotypes in Bladder Cancer

“…Despite the prominent role of TGF-b in regulating multiple cancer processes, therapies targeting the TGF-b pathway have not been well explored (10). With the improvement of genomic sequencing methods, more and more genomic signatures have been created to predict the prognosis and therapeutic opportunities for cancers (8,23,24). In BLCA, Stojnev et al explored the roles of three key components (TGF-b1, Smad2, and Smad4) of the canonical TGFb pathway in predicting the prognosis (25).…”

A Novel Assessment Model Based on Molecular Subtypes of Hypoxia-Related LncRNAs for Prognosis of Bladder Cancer

“…Therefore, hypoxia as a factor that alters the tumor characteristic microenvironment can accelerate tumor metastasis and enhance drug resistance ( Zandberg et al, 2021 ). Numerous studies have confirmed that there is a hypoxic microenvironment in most solid tumors, including BCa, and the expression of hypoxia-related genes will affect the TME, the efficacy of therapeutic drugs, and patient prognosis ( Yang et al, 2017 ; Liu et al, 2021 ). However, some previous studies have verified that some HRLs will also affect tumor progression, and the HRL risk model can also predict the patient prognosis well and has an effect on clinical therapy ( Shao et al, 2021 ; Zhang et al, 2021 ).…”

“…With the development of gene-sequencing technology, many hypoxia-related signatures have been established in multiple tumors to predict patient prognosis and treatment efficacy, such as immunotherapy and chemotherapy response ( Shao et al, 2021 ; Sun et al, 2021a ). In BCa, multiple hypoxia-related gene signatures were developed and validated to predict prognosis and TME immune characteristics ( Yang et al, 2017 ; Liu et al, 2021 ). In recent years, with the successful application of immunotherapy in tumors, an increasing number of people have begun to pay attention to the clinical value of immune checkpoints, such as anti-PD-L1/PD-1 therapy.…”

“…In recent years, with the successful application of immunotherapy in tumors, an increasing number of people have begun to pay attention to the clinical value of immune checkpoints, such as anti-PD-L1/PD-1 therapy. It is worth noting that the effect of immunotherapy is closely related to the TME ( Hu et al, 2021 ; Liu et al, 2021 ). Liu et al (2021) developed and validated a hypoxia risk score that was related to the expression of several immune checkpoints, such as PD-L1, PD-1, CTLA-4, and LAG-3, by analyzing the BCa TME.…”

“…It is worth noting that the effect of immunotherapy is closely related to the TME ( Hu et al, 2021 ; Liu et al, 2021 ). Liu et al (2021) developed and validated a hypoxia risk score that was related to the expression of several immune checkpoints, such as PD-L1, PD-1, CTLA-4, and LAG-3, by analyzing the BCa TME.…”