Investigating the Role of B Lymphocytes in Urinary Bladder Tumor Development
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Authors
RahimiKazerouni, Sadaf
Date
Type
thesis
Language
eng
Keyword
Bladder cancer , B lymphocyte , Urothelial carcinoma , Tumor immune microenvironment
Alternative Title
Abstract
Urinary bladder cancer (BC) is a highly prevalent disease with 25% of the incident cases presenting muscle invasive BC (MIBC). Immune cell populations in the tumor immune microenvironment (TIME) influence BC progression and response to therapy. While immune cells such as tumorassociated macrophages (TAMs) and T cells have been widely studied in BC, the role of B cells remains unclear. This study aimed to examine the role of B cells, particularly, atypical B cells (ABCs) in the progression of BC. As such, we investigated the impact of B cell depletion on BC progression in a carcinogen-induced murine model. Sex differences in the TIME and disease progression were observed following B cell depletion in carcinogen exposed mice. Female mice exhibited increased number of ABCs in their spleen, while males showed near complete ABC depletion. Spatial profiling of bladders post depletion depicted clear sex differences with female mice having higher total B cell and ABC frequencies. B cell depletion also increased the splenic total and cytotoxic T cell populations in both female and male mice, indicating enhanced antitumor immunity. B cell depletion reduced inflammation and delayed cancer progression, specifically, in female mice. However, discontinuation of depletion during carcinogen exposure resulted in accelerated tumor invasion and decreased survival. Treatment of B cells with TLR7 agonist augmented ABC differentiation and cell survival. Spatial profiling of bladders with muscle invasion revealed higher density of ABCs and lower density of T cells in B cell depleted female mice compared to non-depleted controls.
Overall, B cell/ABC depletion appears to temporarily induce a favorable immune microenvironment by eliminating the exhausted populations and reactivating lymphopoiesis. However, in the continued presence of carcinogen, the rejuvenated B cell pool differentiates towards an immunosuppressive ABC phenotype after discontinuing depletion, enabling cancer progression. The more pronounced impact seen in females may be due to higher initial baseline ABC levels and increased response to cell death-induced TLR7 activation. These findings provide evidence that ABCs can be contributing factors to an immunosuppressive TIME that enables BC progression. This study elucidates B cell and ABC involvement in the progression of BC, laying the groundwork for combination immunotherapies targeting ABCs to improve treatment outcomes in a sex-specific manner.
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ProQuest PhD and Master's Theses International Dissemination Agreement
Intellectual Property Guidelines at Queen's University
Copying and Preserving Your Thesis
This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.