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Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma.

ABSTRACT: Objective: Resistance to immune checkpoint inhibitors (ICIs) has been a massive obstacle to ICI treatment in metastatic urothelial carcinoma (MUC). Recently, increasing evidence indicates the clinical importance of the association between hypoxia and immune status in tumor patients. Therefore, it is necessary to investigate the relationship between hypoxia and prognosis in metastatic urothelial carcinoma. Methods: Transcriptomic and clinical data from 348 MUC patients who underwent ICI treatment from a large phase 2 trial (IMvigor210) were investigated in this study. The cohort was randomly divided into two datasets, a training set (n = 213) and a testing set (n = 135). Data of hypoxia-related genes were downloaded from the molecular signatures database (MSigDB), and screened by univariate and multivariate Cox regression analysis to construct a prognosis-predictive model. The robustness of the model was evaluated in two melanoma cohorts. Furthermore, an external validation cohort, the bladder cancer cohort, from the Cancer Genome Atlas (TCGA) database, was t used to explore the mechanism of gene mutation, immune cell infiltration, signaling pathway enrichment, and drug sensitivity. Results: We categorized patients as the high- or low- risk group using a four-gene hypoxia risk model which we constructed. It was found that patients with high-risk scores had significantly worse overall survival (OS) compared with those with low-risk scores. The prognostic model covers 0.71 of the area under the ROC curve in the training set and 0.59 in the testing set, which is better than the survival prediction of MUC patients using the clinical characteristics. Mutation analysis results showed that deletion mutations in RB1, TP53, TSC1 and KDM6A were correlated with hypoxic status. Immune cell infiltration analysis illustrated that the infiltration T cells, B cells, Treg cells, and macrophages was correlated with hypoxia. Functional enrichment analysis revealed that a hypoxic microenvironment activated inflammatory pathways, glucose metabolism pathways, and immune-related pathways. Conclusion: In this investigation, a four-gene hypoxia risk model was developed to evaluate the degree of hypoxia and prognosis of ICI treatment, which showed a promising clinical prediction value in MUC. Furthermore, the hypoxia risk model revealed a close relationship between hypoxia and the tumor immune microenvironment.

SUBMITTER: Hong S

PROVIDER: S-EPMC8657403 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective: This study used homologous recombination (HR) related signatures to develop a clinical prediction model for screening immune checkpoint inhibitors (ICIs) advantaged populations and identify hub genes in advanced metastatic urothelial carcinoma. Methods: The single-sample gene enrichment analysis and weighted gene co-expression network analysis were applied to identify modules associated with immune response and HR in IMvigor210 cohort samples. The principal component analysis was utilized to determine the differences in HR-related module gene signature scores across different tissue subtypes and clinical variables. Risk prediction models and nomograms were developed using differential gene expression analysis associated with HR scores, least absolute shrinkage and selection operator, and multivariate proportional hazards model regression. Additionally, hub genes were identified by analyzing the contribution of HR-related genes to principal components and overall survival analysis. Finally, clinical features from GSE133624, GSE13507, the TCGA, and other data sets were analyzed to validate the relationship between hub genes and tumor growth and mutation. Results: The HR score was significantly higher in the complete/partial response group than in the stable/progressive disease group. The majority of genes associated with HR were discovered to be involved in the cell cycle and others. Genomically unstable, high tumor level, and high immune level samples all exhibited significantly higher HR score than other sample categories, and higher HR scores were related to improved survival following ICIs treatment. The risk scores for AUNIP, SEPT, FAM72D, CAMKV, CXCL9, and FOXN4 were identified, and the training and verification groups had markedly different survival times. The risk score, tumor neoantigen burden, mismatch repair, and cell cycle regulation were discovered to be independent predictors of survival time following immunotherapy. Patients with a high level of expression of hub genes such as EME1, RAD51AP1, and RAD54L had a greater chance of surviving following immunotherapy. These genes are expressed at significantly higher levels in tumors, high-grade cancer, and invasive cancer than other categories, and are associated with TP53 and RB1 mutations. Conclusion: HR-related genes are upregulated in genomically unstable samples, the survival time of mUC patients after treatment with ICIs can be predicted using a normogram model based on HR signature.

Project description:Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC. Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score. Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts. Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.

Project description:BackgroundImmunogenic cell death (ICD) has been categorized as a variant of regulated cell death that is capable of inducing an adaptive immune response. A growing body of evidence has indicated that ICD can modify the tumor immune microenvironment by releasing danger signals or damage-associated molecular patterns (DAMPs), potentially enhancing the efficacy of immunotherapy. Consequently, the identification of biomarkers associated with ICD that can classify patients based on their potential response to ICD immunotherapy would be highly advantageous. Therefore the goal of the study is to better understand and identify what patients with bladder urothelial carcinoma (BLCA) will respond to immunotherapy by analyzing ICD signatures and investigate ICD-related prognostic factors in the context of BLCA.MethodsThe data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases regarding BLCA and normal samples was categorized based on ICD-related genes (IRGs). Specifically, we conducted an immunohistochemical (IHC) experiment to validate the expression levels of Calreticulin (CALR) in both tumor and adjacent tissues, and evaluated its prognostic significance using the Kaplan-Meier (KM) curve. Subsequently, the samples from TCGA were divided into two subtypes using consensus clustering. To obtain a more comprehensive comprehension of the biological functions, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The calculation of immune landscape between two subtypes was performed through ESTIMATE and CIBERSORT. Risk models were constructed using Cox and Lasso regression and their prognosis predictive ability was evaluated using nomogram, receiver operating characteristic (ROC), and calibration curves. Finally, Tumor Immune Dysfunction and Exclusion (TIDE) algorithms was utilized to predict the response to immunotherapy.ResultsA total of 34 IRGs were identified, with most of them exhibiting upregulation in BLCA samples. The expression of CALR was notably higher in BLCA compared to the adjacent tissue, and this increase was associated with an unfavorable prognosis. The differentially expressed genes (DEGs) associated with ICD were linked to various immune-related pathways. The ICD-high subtypes exhibited an immune-activated tumor microenvironment (TME) compared to the ICD-low subtypes. Utilizing three IRGs including CALR, IFNB1, and IFNG, a risk model was developed to categorize BLCA patients into high- and low-risk groups. The overall survival (OS) was considerably greater in the low-risk group compared to the high-risk group, as evidenced by both the TCGA and GEO cohorts. The risk score was identified as an independent prognostic parameter (all p < 0.001). Our model demonstrated good predictive ability (The area under the ROC curve (AUC), AUC1-year= 0.632, AUC3-year= 0.637, and AUC5-year =0.653). Ultimately, the lower risk score was associated with a more responsive immunotherapy group.ConclusionThe potential of the ICD-based risk signature to function as a marker for evaluating the prognosis and immune landscape in BLCA suggests its usefulness in identifying the suitable population for effective immunotherapy against BLCA.

Project description:Urothelial cancer (UC) is one of the common refractory tumors and chemotherapy is the primary treatment for it. The advent of immune checkpoint inhibitors (ICI) has facilitated the development of treatment strategies for UC patients. To screen out UC patients sensitive to ICI, researchers have proposed that PD-L1, tumor mutation burden and TCGA molecular subtypes can be used as predictors of ICI efficacy. However, the performance of these predictors needs further validation. We need to identify novel biomarkers to screen out UC patients sensitive to ICI. In our study, we collected the data of two clinical cohorts: the ICI cohort and the TCGA cohort. The result of the multivariate Cox regression analysis showed that glycogen metabolism score (GMS) (HR = 1.26, p = 0.017) was the negative predictor of prognosis for UC patients receiving ICI treatment. Low-GMS patients had a higher proportion of patients achieving complete response or partial response to ICI. After the comparison of gene mutation status between high-GMS and low-GMS patients, we identified six genes with significant differences in mutation frequencies, which may provide new directions for potential drug targets. Moreover, we analyzed the immune infiltration status and immune-related genes expression between high-GMS and low-GMS patients. A reduced proportion of tumor-associated fibroblasts and elevated proportion of CD8+ T cells can be observed in low-GMS patients while several immunosuppressive molecules were elevated in the high-GMS patients. Using the sequencing data of the GSE164042 dataset, we also found that myeloid-derived suppressor cell and neutrophil related signature scores were lower in α-glucosidase knockout bladder carcinoma cells when compared to the control group. In addition, angiogenesis, classic carcinogenic pathways, immunosuppressive cells related pathways and immunosuppressive cytokine secretion were mainly enriched in high-GMS patients and cell samples from the control group. Finally, we suspected that the combination treatment of ICI and histone deacetylase inhibitors may achieve better clinical responses in UC patients based on the analysis of drug sensitivity data. In conclusion, our study revealed the predictive value of GMS for ICI efficacy of UC patients, providing a novel perspective for the exploration of new drug targets and potential treatment strategies.

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Hypoxic Characteristic Genes Predict Response to Immunotherapy for Urothelial Carcinoma.

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