Investigating Sexual Dimorphism in Murine Bladders and Plasmacytoid Dendritic Cell Response to BCG and STING Pathway Activation
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Authors
Hamade, Ali
Date
Type
thesis
Language
eng
Keyword
BCG , Sexual dimorphism , Bladder cancer , Non-muscle invasive bladder cancer , Ageing
Alternative Title
Abstract
The incidence of urothelial carcinoma of the bladder (UCB) is four times higher in males than females; however, females tend to present with a more aggressive disease, a poorer response to immunotherapy, and suffer worse clinical outcomes. Treatment with Bacillus Calmette-Guerin (BCG) immunotherapy is the mainstay for non-muscle invasive bladder cancer (NMIBC) treatment. Unfortunately, over 50% of patients do not respond optimally and exhibit recurrence or progression to an invasive disease. Recent findings have demonstrated sexual dimorphism in the tumor immune microenvironment of NMIBC and associated clinical outcomes. However, a significant gap in knowledge remains with respect to the current pre-clinical modeling approaches and, more precisely recapitulating these differences towards therapeutic development.
With similarities in mucosal immune physiology between humans and mice, we evaluated the sex and age-related physiological immune alterations in healthy murine bladders. The plasmacytoid dendritic cells (pDCs), the most potent type 1 interferon (IFN1) producers, exhibit sex differences and age-related decline in function. Towards rescuing the deficiency in inducing a potent IFN1 response via synergistic activation of the Stimulator of Interferon Genes (STING) pathway with BCG, in vitro evaluations of pDCs, from young and old female mice were performed.
Bulk-RNA sequencing and multiplex immunofluorescence based spatial immune profiling of healthy murine bladders from male and female mice of the age groups spanning young to old, showed a highly altered immune landscape that exhibited sex and age associated differences, particularly in the context of B cell associated responses. Spatial profiling using markers specific to macrophages, T lymphocytes, B lymphocytes, activated dendritic cells, high endothelial venules, inflammatory cells and the PD-L1 immune checkpoint, showed sex and age associated differences. Bladders from older female mice showed a higher number of tertiary lymphoid structures compared to both young female and male equivalents. Bone marrow-derived pDCs from older females secreted higher CXCL10, Il-6, TNF-α, CCL5, MIP-1α, CXCL1, MIP-1β, MIP-2 in response to BCG infection and STING agonist treatment.
These findings support the incorporation of sex and age as factors in pre-clinical modeling of NMIBC and will potentially advance the field of immunotherapeutic drug development to improve clinical outcomes in NMIBC.
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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.