Wednesday, February 5, 2025
2/5/2025
Project Summary The prostate is a secretory gland that interacts with the urinary tract microbiome, including bacterial and viral pathogens, which can cause inflammation conducive to the development of prostate cancer. Prostate cancer, which is often proceeded by prostatitis, affects 1 in 8 men during their lifetime, resulting in around 34,500 deaths annually. Despite the link between long-term inflammation and cellular transformation, the resident immune cells within the prostate tissue, in particular CD8+ resident memory T cells (TRM), have not been characterized. As CD8+ T cells play key roles in controlling inflammation and tumor growth, understanding the mechanisms by which prostate-resident memory CD8+ T cells are formed and maintained in response to infection is critical to understanding prostate biology. A detailed understanding of the regulatory programs and transcriptional networks that govern T cell adaptations to residency in the prostate tissue will inform the ability to ‘program’ tissue-tailored immune responses, where immune cells that promote or regulate inflammation can be transcriptionally engineered for trafficking to, retention in, and function within the prostate tissue. Therefore, understanding the tissue-specific adaptations of T cells to the prostate environment will inform strategies to treat prostate-specific disease, including prevention and treatment of prostate inflammation, prostate tumorigenesis, and immunotherapy for prostate tumors. Importantly, our preliminary work establishes that TRM possess tissue- specific adaptation to unique tissues. Understanding the cues regulating prostate TRM is the focus of my F31 application. We find memory CD8+ T cells that express markers consistent with tissue residency within the prostate epithelium up to 500 days following LCMV Armstrong infection, demonstrating the generation of a stable TRM population. These prostate TRM have features that are distinct from other TRM populations, including expression of functional nuclear androgen receptor (AR) and unique dynamics of the retention molecule CD103. We hypothesize these features are part of prostate-specific TRM adaptations. To test this hypothesis, I propose two independent aims. The first aim will examine the dependence of prostate TRM on the cytokine TGFβ and the functional and protective capacity of prostate TRM. The second aim will determine the role of androgen receptor in prostate TRM differentiation and homeostasis. In summary, the goal of this proposal is to provide insight into the environmental cues that impact prostate TRM formation. This application outlines my training plan, which has been discussed and curated with Dr. Ananda Goldrath and includes advanced coursework, training in new techniques, and training in science writing and communication. The research and training plan outlined in this proposal will provide me with the skills necessary to develop into an independent scientist prepared to pursue a career in academic research.
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