Gene expression analysis of bladder cancer cell line, its BCG resistant and AR knockdown subline.
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PROVIDER: PRJNA623893 | ENA |
REPOSITORIES: ENA
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Project description:BCG resistant and AR konckdown subline from UMUC3 were compared with the original cell line.
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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.
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Project description:The treatment of advanced prostate cancer has been transformed by novel antiandrogen therapies such as enzalutamide. Using the LnCaP/AR xenograft model, we identified induction of glucocorticoid receptor (GR) expression as a common feature of drug resistant tumors. From a resistant xenograft tumor, we derived a GR expressing resistant subline called LREX' which maintains the resistant phenotype. mRNA expression was used to characterize resistant tissues.
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Project description:Intravesical BCG Immunotherapy is the standard of care in treating non-muscle invasive bladder cancer, yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. While prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer is characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. By contrast, treatment with intravesical BCG leads to a large, transient rise in the CD4+ T cell population in the urothelium, and is both more effective and immunogenic compared to intravesical chemotherapy. Interestingly, whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that while BCG induces T cell recruitment to the bladder, the T cell phenotype does not markedly change, implying that combining T cell activating agents with BCG might improve clinical activity.
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Project description:Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice to stratify future urothelial cancer patient treatment strategies.
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Project description:Patients with high-risk non-muscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical BCG therapy and may have a dismal outcome. Resistance mechanisms to such immunotherapy remain misunderstood. Here, using cancer cell lines, freshly resected human bladder tumors and cohorts of bladder cancer patients pre- and post-BCG therapy, we demonstrate two distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a post-transcriptional downregulation of HLA-I membrane expression via an inhibition of the autophagy flux. Patients with HLA-I deficient cancer cells post-BCG therapy displayed a myeloid immunosuppressive tumor microenvironment with epithelial-to-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I proficient cancer cells post-BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines and inhibitory immune checkpoint molecules. Those patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse post-BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts dismal prognosis. Cancer cells HLA-I scoring by immunohistochemistry (IHC) staining can be easily implemented by pathologists in routine practice to stratify future urothelial cancer patient treatment strategies.
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2013-12-27 | E-GEOD-51873 | biostudies-arrayexpress
Project description:The paper describes a model on the Dynamics of Immune Checkpoints, Immune System, and BCG in the Treatment of Superficial Bladder Cancer.
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This model is described in the article:
Dynamics of Immune Checkpoints, Immune System, and BCG in the Treatment of Superficial Bladder Cancer
Farouk Tijjani Saad, Evren Hincal, and Bilgen Kaymakamzade
Computational and Mathematical Methods in Medicine, vol. 2017, no. 3573082
Abstract:
This paper aims to study the dynamics of immune suppressors/checkpoints, immune system, and BCG in the treatment of superficial bladder cancer. Programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and transforming growth factor-beta (TGF-b) are some of the examples of immune suppressors/checkpoints. They are responsible for deactivating the immune system and enhancing immunological tolerance. Moreover, they categorically downregulate and suppress the immune system by preventing and blocking the activation of T-cells, which in turn decreases autoimmunity and enhances self- tolerance. In cancer immunotherapy, the immune checkpoints/suppressors prevent and block the immune cells from attacking, spreading, and killing the cancer cells, which leads to cancer growth and development. We formulate a mathematical model that studies three possible dynamics of the treatment and establish the effects of the immune checkpoints on the immune system and the treatment at large. Although the effect cannot be seen explicitly in the analysis of the model, we show it by numerical simulations.
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2024-09-02 | BIOMD0000000746 | BioModels
Project description:Patients with high-risk non-muscle-invasive bladder carcinoma (NMIBC) frequently relapse after standard BCG immunotherapy and have a dismal outcome after progression to muscle-invasive bladder carcinoma (MIBC). Although BCG induces potent inflammatory responses upon intravesical instillations, the mechanisms of tumor resistance to such immunotherapy remain elusive. We performed a longitudinal immune profiling of a cohort of MIBC pre- and post BCG therapy with gene and protein expression analysis to establish correlations with 5 year clinical follow up. Here, we demonstrate two distinct patterns of BCG-induced immunosubversion, which include acquired immune resistance and tumor-cell intrinsic resistance. Firstly, intracellular BCG infection of a subset of urothelial carcinoma cells downregulated HLA-I expression and induced epithelial to mesenchymal transition (EMT) characteristics. BCG treated tumors exhibiting such HLA class I loss displayed an immune desert tumor microenvironment dominated by myeloid immunosuppressive cells. Such patients presented with early cancer relapses and a bad outcome. Conversely, BCG-treated tumors which did not lose HLA class I antigens at relapse displayed an immune escape mechanism dominated by a Th1 pattern with high expression of inhibitory checkpoints and exhaustion markers. Such patients had a favorable outcome upon second surgery. We surmise that HLA class I expression does not result from immunoediting but rather from an EMT process associated to myeloid immunosuppression that predicts dismal prognosis.
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Project description:Full title: Predictive Gene Signatures as Strong Prognostic Indicators of the Effectiveness of Bacillus Calmetteâ??Guérin (BCG) Immunotherapy in Primary pT1 Bladder Cancers Intravesical BCG immunotherapy is effective in prevention of recurrence and progression in many cases of non-muscle invasive bladder cancer, but many patients fail to respond. This study identified predictive gene signatures in primary pT1 bladder cancer with BCG immunotherapy. Fourty-Eight patients with primary pT1 bladder cancer treated with BCG immunotherapy were used. Microarray gene expression analysis of the 48 primary bladder cancers was carried out. Predictive gene signatures were individually selected based on the recurrence and progression status. Among 43,148 unique genes, 424 and 287 candidate predictive genes that could predict recurrence and progression, respectively, were selected. Time to recurrence or progression was shorter for patients with poor-predictive gene signatures than good-predictive gene signatures (log-rank test, p <0.001, respectively). Validation of predictive gene signatures with RT-PCR was nearly identical to those of microarray (log-rank test, p <0.05, respectively). In multivariate regression analysis, predictive gene signatures were the only independent predictors of recurrence (HR 3.38, p = 0.048) or progression (HR 10.49, p = 0.048) in validation cohorts. Predictive gene signatures have strong diagnostic value for determining the response to intravesical BCG immunotherapy in primary pT1 bladder cancer. Keywords: Gene expression, Bladder cancer, BCG Total RNA, extracted from the fresh frozen tissues of 48 pT1 bladder cancers, was isolated by TRIzol reagent (Life Technologies, NY, USA), according to the manufacturer's protocol. The quality and integrity of the RNA were confirmed by agarose gel electrophoresis and ethidium bromide staining, followed by visual examination under ultraviolet light. Five-hundred nanograms of total RNA were used for labeling hybridization according to the manufacturerâ??s protocol (Illumina HumanWG-6 BeadChip, version 2, Illumina, Inc., San Diego, CA, USA). Arrays were scanned with an Illumina Bead Array Reader confocal scanner (BeadStation 500GXDW; Illumina, Inc.) according to the manufacturer's instructions. Initial microarray gene expression data were obtained using Bead Studio software with gene expression analysis module (version 3.1.3, Illumina, Inc.).
2010-04-07 | E-GEOD-19423 | biostudies-arrayexpress