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Prostate stromal fibroblasts as immune regulators and effectors

Reilly, Katrina (2017) Prostate stromal fibroblasts as immune regulators and effectors. PhD thesis, University of York.

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Prostate cancer (PCa) is the most common cancer diagnosis in males and the second leading cause of cancer related male deaths. Local microenvironments containing stromal fibroblasts are vitally important in the normal development and homeostatic regulation of the prostate, and have key roles in supporting prostate cancer progression. Local chronic inflammation has been associated with the development of prostate cancer. The potential impact of local immune cell derived inflammatory mediators on prostate stromal and epithelial/tumour cells have been studied, however the reciprocal impact on infiltrating immune cells has not been fully explored. Advancements in immunotherapy through clinical applications in checkpoint molecule inhibition have led to significant progress in the treatment of melanoma and lung cancer in recent years. However, for unknown reasons, immunotherapies thus far have widely failed to have therapeutic efficacy in prostate cancer patients. By utilising primary human prostate tissue samples from patients with benign prostatic hyperplasia (BPH) or PCa using both in vitro culture systems combined with gene expression profile analysis, imaging and flow cytometry, it has been shown that prostate stromal cells exhibit a conserved capacity to interact with local immune cells. Prostate stromal cells potently express an array of molecules known to negatively regulate immune cells, either endogenously, or in response to local immune activity through TGF-β, IDO and PD-L1. The expression of these molecules drives inhibition of local anti-tumour T cells and ultimately, tumour immune evasion. Furthermore, an experimental protocol to analyse the prostate infiltrating immune cells by flow cytometry was developed and used to demonstrate preliminary evidence for an enrichment of cytotoxic T lymphocytes in the tissue compared to peripheral blood. Importantly, these T cells have an increased surface expression of PD-1, the receptor that binds PD-L1 to induce T cell inhibition. Prostate tissue contains large numbers of stromal fibroblasts, even in cases of high-grade cancer. This study indicates prostate stromal cells tip the balance toward immunosuppression, which in the context of prostate cancer may lead to tumour immune escape. This is an important consideration for future studies in the field of immunotherapy in prostate cancer, since prostate infiltrating immune cells reside in the stromal compartment. Therefore, the success of PCa immunotherapy likely relies on targeting tumour fibroblasts.

Item Type: Thesis (PhD)
Academic Units: The University of York > Biology (York)
Depositing User: Unnamed user with email k.reilly@leeds.ac.uk
Date Deposited: 06 Jun 2017 11:32
Last Modified: 25 May 2019 00:18
URI: http://etheses.whiterose.ac.uk/id/eprint/17466

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