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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE199471 | GEO | 2022/05/05

REPOSITORIES: GEO

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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.

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.

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BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer [RNA-seq]

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