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Intravesical BCG induces CD4+ T Cell Expansion in a Clinically Relevant Immune Competent Model of Bladder Cancer

ABSTRACT: 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.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE93940 | GEO | 2017/08/31

SECONDARY ACCESSION(S): PRJNA362873

REPOSITORIES: GEO

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Project description:Full title: Predictive Gene Signatures as Strong Prognostic Indicators of the Effectiveness of Bacillus Calmetteâ??GuÃ©rin (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.).

Project description:The paper describes a model on the Dynamics of Immune Checkpoints, Immune System, and BCG in the Treatment of Superficial Bladder Cancer. Created by COPASI 4.25 (Build 207) 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. This model is hosted on BioModels Database and identified by: MODEL1907100001. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:Radiation and BCG instillations are used clinically for treatment of urothelial carcinoma, but the precise mechanisms by which they activate an immune response remain elusive. The role of the cGAS-STING pathway has been implicated in both BCG and radiation-induced immune response however comparison of STING-pathway molecules and immune landscape following treatment in urothelial carcinoma has not be performed. We therefore comprehensively analyzed the local immune response in the bladder tumor microenvironment following radiotherapy and BCG instillations in a well-established spontaneous murine model of urothelial carcinoma to provide insight into activation of STING-mediated immune response. Mice were exposed to the oral carcinogen, BBN, for 12 weeks prior to treatment with a single 15Gy dose of radiation or 3 intravesical instillations of BCG (1x108 CFU). At sacrifice, tumors were staged by a urologic pathologist and effects of therapy on the immune microenvironment were measured using NanoString Myeloid Innate Immunity Panel and immunohistochemistry. Clinical relevance was established by measuring immune biomarker expression of cGAS and STING on a human tissue microarray consisting of BCG-treated non-muscle invasive urothelial carcinomas. BCG instillations in the murine model elevated STING and downstream STING-induced interferon and pro-inflammatory molecules, intratumoral M1 macrophage and T-cell accumulation, and complete tumor eradication. In contrast, radiotherapy caused no changes in STING pathway or innate immune gene expression; rather, it induced M2 macrophage accumulation and elevated FoxP3 expression characteristic of immunosuppression. In human non-muscle invasive bladder cancer, STING protein expression was elevated at baseline in patients who responded to BCG therapy and increased further after BCG therapy. Overall, these results show that STING pathway activation plays a key role in effective BCG-induced immune response and strongly indicate that the effects of BCG on the bladder cancer immune microenvironment are more beneficial than those induced by radiation.

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Intravesical BCG induces CD4+ T Cell Expansion in a Clinically Relevant Immune Competent Model of Bladder Cancer

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