Combination Biomarker of Immune Checkpoints Predict Prognosis of Urothelial Carcinoma.
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ABSTRACT:
SUBMITTER: Tsai CY
PROVIDER: S-EPMC8772792 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Muscle-invasive bladder urothelial carcinoma (MIBC) is characteristic of high mortality and high recurrence. Distinguishing the prognostic risk of MIBC at the molecular level of miRNA expression is rarely performed and thus of great significance for the management and treatment of MIBC in clinics. Adaptive lasso Cox's proportional hazards model was used to explore the relationship between differential expression miRNAs (DEmiRNAs) and MIBC survival. Furthermore, we evaluated the epithelial-mesenchymal transition (EMT) score and immune infiltration abundance by exploring EMT signature genes and TIMER database, respectively. A total of 8 DEmiRNAs were detected to be associated with the survival rate of MIBC by using the lasso Cox algorithm. Through the linear combination of these 8 DEmiRNAs, we constructed a calculated marker, which could be used to distinguish the prognosis risk in both TCGA dataset (HR = 2.03, 95% CI = (1.47, 2.83)) and independent validation dataset (HR = 7.74, 95% CI = (1.05, 56.93)). Meanwhile, the constructed marker had reasonably high predictive values of the AUC (area under the curve) in the TCGA dataset and validation dataset being 0.73 and 0.63, respectively. In addition, we observed that the expression values of let-7c, miR-100, and miR-145 were associated with EMT score and the abundance of macrophage in tumor tissue as well. This newly identified risk score signature based on the combination of 8 miRNAs could significantly predict the prognostic risk of MIBC and might provide insight into immunotherapy and targeted therapy of MIBC.
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Project description:Studies on immune checkpoint inhibitors targeting B7-CD28 family pathways in esophageal squamous cell carcinoma (ESCC) have shown promising results. However, a comprehensive understanding of B7-CD28 family members in ESCC is still limited. This study aimed to construct a novel B7-CD28 family-based prognosis system to predict survival in patients with ESCC. We collected 179 cases from our previously published microarray data and 86 cases with qPCR data. Specifically, 119 microarray data (GSE53624) were used as a training set, whereas the remaining 60 microarray data (GSE53622), all 179 microarray data (GSE53625) and an independent cohort with 86 qPCR data were used for validation. The underlying mechanism and immune landscape of the system were also explored using bioinformatics and immunofluorescence. We examined 13 well-defined B7-CD28 family members and identified 2 genes (ICSOLG and HHLA2) with the greatest prognostic value. A system based on the combination HHLA2 and ICOSLG (B7-CD28 signature) was constructed to distinguish patients as high- or low-risk of an unfavorable outcome, which was further confirmed as an independent prognostic factor. As expected, the signature was well validated in the entire cohort and in the independent cohort, as well as in different clinical subgroups. The signature was found to be closely related to immune-specific biological processes and pathways. Additionally, high-risk group samples demonstrated high infiltration of Tregs and fibroblasts and distinctive immune checkpoint panels. Collectively, we built the first, practical B7-CD28 signature for ESCC that could independently identify high-risk patients. Such information may help inform immunotherapy-based treatment decisions for patients with ESCC.
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Project description:Background:OX40 and OX40 ligand (OX40L), as essential immune checkpoint (IC) modulators, are highly correlated with cancer immunity regulation as well as tumor microenvironment (TME). Immunotherapy showed outstanding advantages in small-cell lung cancer (SCLC) therapy. However, functions and clinical significance of OX40 and OX40L in SCLC were not clear yet. Materials and Methods:SCLC samples of 143 patients were collected for immunohistochemistry (IHC) or whole-exome sequencing (WES). We comprehensively explored the expression and mutation of OX40/OX40L in SCLC, and systematically linked OX40/OX40L with TME. Results:The expression of OX40/OX40L on tumor cells and tumor-infiltrating lymphocytes (TILs) was found in the IHC cohort and verified in other cohorts with SCLC tissues and cell lines. The results showed co-expression patterns among OX40/OX40L, other ICs, and T-cell markers. The WES data suggested that OX40/OX40L mutation is rare in SCLC (<5%). Patients with positive OX40 protein expression on TILs showed substantially higher recurrence-free survival than those with negative expression (p=0.009). The external dataset also indicated that high OX40/OX40L expression was correlated with better prognosis [overall survival: OX40, p<0.001; OX40L, p=0.019]. Importantly, activation of immunity and high infiltration of CD4(+) and CD8(+) T cells were observed in the high OX40/OX40L expression group. Conclusions:Collectively, this work highlighted the significance of OX40 and OX40L in prognosis and TME cell infiltration characterization of SCLC. Evaluating the OX40/OX40L-expression levels of individual patients with SCLC might contribute to guiding more precise therapy.
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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.
| S-EPMC9086193 | biostudies-literature
Project description:AimsThere are limited data examining the role of immune checkpoint (IC) ligands in the pathophysiology of heart failure (HF). Therefore, we explore this in three HF animal models and in three different human cohorts (healthy, stable, and worsening HF).Methods and resultsTranscriptomic analyses of cardiac tissue of three different HF mouse models revealed differentially expressed IC receptors and their ligands compared with control mice. Based on this observation, serum levels of three well-known IC ligands (i.e. sPD-L1, sPD-L2 and galectin-9) were measured in stable HF patients from the Vitamin D Chronic Heart Failure (VitD-CHF) study (n = 101), as well as healthy individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (n = 58). sPD-L1, sPD-L2, and galectin-9 were all associated with New York Heart Association classification. In multivariate linear regression analyses, all three IC ligands were associated with galectin-3 (β = 0.230, β = 0.283, and β = 0.304, respectively). sPD-L1 and galectin-9 were also associated with hs-troponin-T (β = 0.386 and β = 0.314). Regarding prognosis, higher serum levels of sPD-L1 and galectin-9 were significantly associated with increased risk for HF hospitalization and all-cause mortality [hazard ratio 1.69 (1.09-2.59) and hazard ratio 1.50 (1.06-2.12)]. Furthermore, the importance of IC ligands was tested in another stage of HF, namely worsening HF patients. In the worsening HF cohort (The BIOlogy Study to Tailored Treatment in Chronic Heart Failure) (n = 2032), sPD-L2 and galectin-9 were associated with New York Heart Association classification and significantly predicted outcome with an increased relative risk of 15% and 20%, after multivariable adjustment, respectively.ConclusionsIC ligands are expressed in cardiac disease models, and serum levels of IC ligands are elevated in HF patients, are associated with disease severity, and significantly predict prognosis. These data indicate a potential role for IC ligands in HF pathogenesis.
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Project description:BackgroundExcept for B7-CD28 family members, more novel immune checkpoints are being discovered. They are closely associated with tumor immune microenvironment and regulate the function of many immune cells. Various cancer therapeutic studies targeting these novel immune checkpoints are currently in full swing. However, studies concerning novel immune checkpoints phenotypes and clinical significance in lung adenocarcinoma (LUAD) are still limited.MethodsWe enrolled 1883 LUAD cases from nine different cohorts. The samples from The Cancer Genome Atlas (TCGA) were used as a training set, whereas seven microarray data cohorts and an independent cohort with 102 qPCR data were used for validation. The immune profiles and potential mechanism of the system were also explored.ResultsAfter univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a novel immune checkpoints-based system (LTA, CD160, and CD40LG) were identified from the training set, which significantly stratified patients into high- and low-risk groups with different survivals. Furthermore, this system has been well validated in different clinical subgroups and multiple validation cohorts. It also acted as an independent prognostic factor for patients with LAUD in different cohorts. Further exploration suggested that high-risk patients exhibited distinctive immune cells infiltration and suffered an immunosuppressive state. Additionally, this system is closely linked to various classical immunotherapy biomarkers.Conclusionwe constructed a novel immune checkpoints-based system for LUAD, which predicts prognosis and immunotherapeutic implications. We believe that these findings will not only aid in clinical management but will also shed some light on screening appropriate patients for immunotherapy.
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Project description:Despite a long history of immunotherapeutic approaches to treatment, most genitourinary malignancies are not cured by existing immunotherapy regimens. More recently, cell surface molecules known as immune checkpoints have become the focus of efforts to develop more effective immunotherapies. Interactions between these molecules and their ligands inhibit the proliferation and function of tumor-specific lymphocytes. A monoclonal antibody blocking 1 of these checkpoints was approved for the treatment of metastatic melanoma and is now being tested in other malignancies. The objective responses seen in these early trials of checkpoint blockade are driving renewed enthusiasm for cancer immunotherapy. There are several ongoing and planned trials in genitourinary malignancies of single-agent inhibitors, as well as combinations targeting multiple checkpoints or adding other types of therapies to checkpoint blockade.
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Project description:BackgroundHepatocellular carcinoma (HCC) is closely associated with the immune microenvironment. To identify the effective population before administering treatment, the establishment of prognostic immune biomarkers is crucial for early HCC diagnosis and treatment.ResultsA total of 335 IRGs identified from 788 overlapping IRGs were associated with the survival of HCC. A prognostic immunoscore model was identified. The Kaplan-Meier survival curves and time-dependent ROC analysis revealed a powerful prognostic performance of immunoscore signature via multi validation. Besides, the immunoscore signature exhibited a better predictive power compared to other prognostic signatures. Gene set enrichment analysis showed multiple signaling differences between the high and low immunoscore group. Furthermore, immunoscore was significantly associated with multiple immune cells and immune infiltration in the tumor microenvironment.ConclusionsWe identified the immunoscore as a robust marker for predicting HCC patient survival.MethodsThree sets of immune-related genes (IRGs) were integrated to identify the overlapping IRGs. Weighted gene co-expression network analysis was performed to obtain the survival-related IRGs. Further, the prognostic immunoscore model was constructed via LASSO-penalized Cox regression analysis. Then the prognostic performance of immunoscore was evaluated. In addition, ESTIMATE and CIBERSORT algorithms were applied to explore the relationship between immunoscore and tumor immune microenvironment.
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Project description:Abnormal proline-rich protein 11 (PRR11) expression is associated with various tumors. However, there are few reports concerning PRR11 with prognostic risk, immune infiltration, or immunotherapy of bladder urothelial carcinoma (BLCA). This study is based on online databases, such as Oncomine, GEPIA, HPA, LinkedOmics, TIMER, ESTIMATE and TISIDB, and BLCA data downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus, we employed an array of bioinformatics methods to explore the potential oncogenic roles of PRR11, including analyzing the relationship between PRR11 and prognosis, tumor mutational burden (TMB), microsatellite instability, and immune cell infiltration in BLCA. The results depict that PRR11 is highly expressed in BLCA, and BLCA patients with higher PRR11 expression have worse outcomes. In addition, there was a significant correlation between PRR11 expression and TMB and tumor immune infiltration. These findings suggest that PRR11 can be used as a potential marker for BLCA patient assessment and risk stratification to improve clinical prognosis, and its potential regulatory mechanism in the BLCA tumor microenvironment and targeted therapy is worthy of further investigation.
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Project description:We found microRNA-133b (miR-133b) was downregulated in urothelial carcinoma of the bladder (UCB) tissues, and it could inhibit the proliferation and induce apoptosis in UCB cells. Consequently, we intend to explore the clinical significance of miR-133b in UCB patients. Expression of miR-133b in 146 UCB specimens and matched adjacent non-neoplastic bladder tissues were measured by quantitative real-time polymerase chain reaction. The overall survival (OS) curve and progression-free survival (PFS) curve were plotted using the Kaplan-Meier method. Prognostic factors for OS and PFS were identified by univariate and multivariate analyses using the Cox proportional hazards regression model. The expression of miR-133b was significantly downregulated in UCB tissues compared with those in adjacent non-neoplastic bladder tissues (P < 0.001). Among UCB patients, low expression of miR-133b significantly correlated with aggressive clinicopathological features. Multivariate analysis indicated that the expression of miR-133b was the independent prognostic factors for predicting PFS (RR: 2.97; 95% CI: 1.78-6.44; P = 0.009) and OS (RR: 4.23; 95% CI: 1.51-11.8; P = 0.011) in patients with UCB. Our study demonstrated that downregulation of miR-133b associated with aggressive clinicopathological features and predicted unfavorable prognosis in patients with UCB, might serve as feasible biomarker for clinical outcome of UCB patients after surgery and potential therapeutic target in the future.
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