Project summary/abstract:
Adult prostate stem cells (PSC) are a rare epithelial progenitor population in the prostate. While essential for
normal homeostasis, they have also been implicated in hyperplasia and cancer initiation.1-7 Inflammation can
fuel hyperplastic diseases through its production of growth factors and cytokines;1, 8, 9 however, the impact of
inflammatory factors on PSC and how PSC interact with infiltrating immune cells is not well studied. To examine
the cross-talk between epithelial PSC and immune cells, the proposed studies will utilize the Prostate Ovalbumin
Expressing Transgenic 3 (POET3), an inducible mouse model of abacterial T cell induced inflammation that
produces epithelial and stromal hyperplasia, functioning as a model for human autoimmune prostatitis.10
Current studies in our lab have taken prostates from inflamed and non-inflamed (naïve) POET3 mice, which
were harvested, digested, and separated by fluorescence-activated cell sorting (FACS) to isolate an enriched
basal PSC population defined as lineage negative (CD45-/CD31-), stem cell antigen-1+, CD49f+ (LSC).11, 12 Single
cell mRNA sequencing comparing freshly isolated LSC from naïve (nLSC) and inflamed (iLSC) mice revealed
differential expression of multiple immune regulatory genes, suggesting a possible role in regulating T cell
response. In vitro suppression assays conducted in our lab confirmed that while neither mature luminal nor nLSC
impacted T cell proliferation, iLSC were able to suppress CD8+ T cells. This effect is independent of recognized
mechanisms, nitric oxide production, IDO1, or PD-L1.13 Notably, prostates from inflamed mice show a marked
enrichment for LSC, suggesting that these cells are protected from T cell attack. Coupled with human BPH data
indicating prominent T cell populations enriched for exhaustion and anergy genes, these findings suggest a
potential novel mechanism of T cell suppression not previously identified in LSC that is induced under
inflammatory conditions, possibly as a tissue protective mechanism.
Thus, we hypothesize that adult basal prostate stem cells are able to harness immune regulatory capabilities
to suppress T cell function and survive T cell mediated attack. Using the POET3 model of autoimmune
inflammation and human BPH samples, studies described herein will explore the T cell suppressive factors
utilized by PSC in vitro and evaluate the impact of PSC suppression in vivo.
The resulting data will provide a foundation for more thorough study of rare stem/progenitor cells in immune
regulation while shedding light on their contribution to epithelial hyperplasia during inflammation.