Immunological hallmarks for clinical response to BCG in bladder cancer
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PROVIDER: EGAS00001004764 | EGA |
REPOSITORIES: EGA
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Project description:Improved risk stratification and predictive biomarkers of treatment response are needed for non–muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. We performed RNA-based profiling by NanoString nCounter on non–muscle-invasive bladder cancer (NMIBC) clinical specimens and found that a novel expression signature of an inflamed tumor microenvironment (TME), but not molecular subtyping, was associated with improved recurrence-free survival after bacillus Calmette-Guérin (BCG) immunotherapy. We further demonstrated that immune checkpoint gene expression was not associated with higher recurrence rates after BCG.
2021-10-05 | GSE185264 | GEO
Project description:Although recent advances in high-throughput technology and data-driven approach have provided many insights into non-muscle invasive bladder cancer (NMIBC), previous studies are still limited in their ability to predict the clinical behavior of NMIBC including response to intravesical therapy. We aim to develop a prognostic index (PI) consisting of a small gene group that predicts the NMIBC progression and response to intravesical bacillus calmette-guérin (BCG) therapy. We analyzed progression-associated genes using Cox regression analysis and validated their predictive values using a fully connected neural network (FNN) algorithm. By applying a pathway enrichment analysis to these genes, a PI system consisting of small core genes for NMIBC progression was developed. Gene expression profiling in NMIBC patients identified a prognostic gene set for predicting NMIBC progression in multiple patient cohorts. Pathway enrichment analysis revealed a 23-gene signature. We incorporated these genes into the PI system, which was a significant prognostic indicator of NMIBC progression. The PI system was shown to be an independent risk factor by a multivariate analysis and subset stratification according to stage and grade. The subset analysis also revealed that the PI system could identify patients who would benefit from BCG immunotherapy. The 23-gene-based PI represents a promising diagnostic tool for identifying high-risk NMIBC patients who would display different clinical behaviors and response to BCG immunotherapy.
2024-02-01 | GSE224248 | GEO
Project description:Trained immunity is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to certain microbial components, altering their responses to future exposures. Intravesical instillation with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant therapy in patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC). HR-NMIBC is associated with a high risk of tumor recurrence and progression to muscle-invasive bladder cancer. The precise immunological mechanisms through which BCG mediates anti-tumor immunity are still unclear. The aim of our study was to investigate the (long-term) induction of trained immunity by repeated BCG instillations in NMIBC patients and elucidate the immunological and epigenetic mechanisms that are involved. Another aim was to assess the relationship between trained immunity response and clinical response of NMIBC patients, in terms of recurrence free survival and progression free survival. To determine whether BCG instillations induce trained immunity in peripheral blood mononuclear cells (PBMCs) we performed a prospective cohort study (‘Tribute’) and isolated PBMCs collected before BCG therapy and at 8 time points during BCG therapy. A total of 17 BCG-naïve HR-NMIBC patients were included. After isolation of PBMCs, monocytes were further purified using an isolation procotol with a percoll gradient. RNA was isolated from these purified monocytes were and used as input for RNA-seq analysis.
2023-03-30 | GSE190529 | GEO
Project description:Trained immunity is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to certain microbial components, altering their responses to future exposures. Intravesical instillation with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant therapy in patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC). HR-NMIBC is associated with a high risk of tumor recurrence and progression to muscle-invasive bladder cancer. The precise immunological mechanisms through which BCG mediates anti-tumor immunity are still unclear. The aim of our study was to investigate the (long-term) induction of trained immunity by repeated BCG instillations in NMIBC patients and elucidate the immunological and epigenetic mechanisms that are involved. Another aim was to assess the relationship between trained immunity response and clinical response of NMIBC patients, in terms of recurrence free survival and progression free survival. To determine whether BCG instillations induce trained immunity in peripheral blood mononuclear cells (PBMCs) we performed a prospective cohort study (‘Tribute’) and isolated PBMCs collected before BCG therapy and at 8 time points during BCG therapy. A total of 17 BCG-naïve HR-NMIBC patients were included. After isolation of PBMCs, monocytes were further purified using an isolation procotol with a percoll gradient. RNA was isolated from these purified monocytes were and used as input for RNA-seq analysis.
2023-03-30 | GSE190528 | GEO
Project description:Trained immunity is the phenomenon whereby innate immune cells such as monocytes or macrophages undergo functional reprogramming after exposure to certain microbial components, altering their responses to future exposures. Intravesical instillation with Bacillus Calmette-Guérin (BCG) is the most effective adjuvant therapy in patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC). HR-NMIBC is associated with a high risk of tumor recurrence and progression to muscle-invasive bladder cancer. The precise immunological mechanisms through which BCG mediates anti-tumor immunity are still unclear. The aim of our study was to investigate the (long-term) induction of trained immunity by repeated BCG instillations in NMIBC patients and elucidate the immunological and epigenetic mechanisms that are involved. Another aim was to assess the relationship between trained immunity response and clinical response of NMIBC patients, in terms of recurrence free survival and progression free survival. To determine whether BCG instillations induce trained immunity in peripheral blood mononuclear cells (PBMCs) we performed a prospective cohort study (‘Tribute’) and isolated PBMCs collected before BCG therapy and at 8 time points during BCG therapy. A total of 17 BCG-naïve HR-NMIBC patients were included. After isolation of PBMCs, monocytes were further purified using an isolation procotol with a percoll gradient. RNA was isolated from these purified monocytes were and used as input for RNA-seq analysis.
2023-08-24 | GSE216062 | GEO
Project description:Background: Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes. Methods: Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders. Tumor samples were subjected to whole-exome RNA sequencing. Gene expression and variant analysis were performed on RNA sequencing to identify changes between BCG durable responders and those that did not respond. Results: Differentially expressed genes in durable responders were input into IPA and identified associated immune related pathways: MIF-mediated Glucocorticoid Regulation, MIF Regulation of Innate Immunity, and p38 MAPK Signaling. The differentially expressed genes were crossed with RNAseq variant analysis to identify genes that had significant changes in both. This analysis identified JCHAIN, S100A7, CLECB, and ANXA10 genes that had snps in non-durable responders vs durable responders and also had significant change in gene expression between these two groups. Conclusions: Differences in the genomic profiles of HG T1 NMIBC tumors exist between those who show durable response to BCG and those who do not. Using pathway analysis, those differences imply upregulation of several interconnected inflammatory pathways among responders. Specific variants identified here are candidates for further study and, if clinically validated, may serve as useful biomarkers in the future.
2021-06-05 | GSE176178 | GEO
Project description:To comprehensively characterize MAIT activation programs responding to different bacteria, we stimulated MAIT cells with E. coli to compare with Bacillus Calmette-Guérin (BCG), which remains the only licensed vaccine and a feasible tool for investigating anti-mycobacterial immunity in humans. Upon sequencing mRNA from the activated and inactivated CD8+ MAIT cells, results demonstrated the altered MAIT cell gene profiles by each bacterium with upregulated expression of activation markers, transcription factors, cytokines, and cytolytic mediators crucial in anti-mycobacterial responses.
2023-04-04 | GSE228089 | GEO
Project description:This experiment explored the transcriptional response of human peripheral blood mononuclear cells (PBMC) isolated from BCG-vaccinated individuals following 6 days of in vitro stimulation with 2x10^5 cfu of different Bacillus Calmette-Guérin (BCG) strains or 100 ng/ml Mycobacterium tuberculosis-derived purified protein derivative (PPD). The BCG strains used were BCG Russia (Russian BCG-I sub-strain), BCG Japan (Tokyo 172 sub-strain), BCG Denmark (Danish 1331 sub-strain) & BCG Pasteur.
2022-01-26 | E-MTAB-11345 | biostudies-arrayexpress
Project description:The current tuberculosis vaccine, Bacillus Calmette-Guérin (BCG), provides insufficient protection. We deleted the NADH dehydrogenase 1 subunit G (nuoG) gene from BCG ΔureC::hly, the most advanced live vaccine candidate in clinical development. Removal of nuoG enhanced co-localisation of LC3 to bacteria in human host cells. BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved efficacy of BCG ΔureC::hly by reducing tuberculosis load in murine lungs 1000-fold.
2016-05-03 | GSE74282 | GEO
Project description:Although the intravesical instillation of Bacillus Calmette-Guerin (BCG) is widely used as adjuvant treatment for nonmuscle-invasive bladder cancers, the clinical benefit is variable across patients, and the molecular mechanisms underlying the sensitivity to BCG administration and disease progression are poorly understood. To establish the molecular signatures that predict the responsiveness and disease progression of bladder cancers treated with BCG, we performed transcriptome sequencing (RNA-seq) for 13 treatment-naïve and 22 post-treatment specimens obtained from 14 bladder cancer patients. To overcome disease heterogeneity, we used non-negative matrix factorization to identify the latent molecular features associated with drug responsiveness and disease progression. At least 12 molecular features were present, among which the immune-related feature was associated with drug responsiveness, indicating that pre-treatment anti-cancer immunity might dictate BCG responsiveness. We also identified disease progression-associated molecular features indicative of elevated cellular proliferation in post-treatment specimens. The progression-associated molecular features were validated in an extended cohort of BCG-treated bladder cancers. Our study advances understanding of the molecular mechanisms of BCG activity in bladder cancers and provides clinically relevant gene markers for evaluating and monitoring patients.
2023-12-25 | GSE244895 | GEO