Wfdc1/ps20 As A Regulator Of Immunity And Growth Within The Prostate.

WFDC1/ps20 as a regulator of immunity and growth within the prostate.

prostrate stromal 20(ps20) encoded by WFDC1, is a 24kDa secreted factor containing the highly conserved whey-acidic protein domain, normally associated with modulating innate-immune responses at mucosal membranes. Ps20 has been shown to exhibit immuno-modulatory and growth inhibitory properties and is highly expressed in the prostate-stroma, as well as the brain, eyes, cardiovascular system and in CD4 T cells, though its expression is frequently lost in tumours. While its physiological function remains largely uncharacterized, ps20 has been shown to be permisivity factor in HIV spread between CD4 T cells, and to be associated with reduced murine hepatitis virus titers through modulation of neutrophil chemo-attractant chemokines and an increased neutrophil response. We investigated the immune-suppressive and anti-tumorigenic properties of ps20 by expression of two WFDC1 cDNAs in prostate-stromal WPMY-1 cells. Conditioned media from ps20 expressing WPMY-1 cells potently inhibits growth of PC-3, DU145 and LNCaP prostate cancer cell lines and halts the proliferation of CD3/28 activated CD4 and CD8 T cells. These functions are retained following depletion of ps20 from the conditioned media suggesting involvement of downstream factors. We performed an unbiased microarray on EV, ps20FL and ps20TR WPMY-1 cells identifying numerous upregulated cytokines, chemokines and growth factors. T cell chemo-attractive CCL5, CXCL1, CCL2 were upregulated along with the growth inhibitory molecules SerpinF1 and COX-2, as were a host innate immune associated cellular factors. We hypothesis therefore that through regulation of a host of lymphotactic and growth-inhibitory paracrine effectors prostate-associated ps20 regulates the infiltration and expansion of T lymphocytes via modulation of the inflammatory milieu in a manner similar to mesenchymal-stromal cells. Further, that ps20 expression in healthy prostate-stroma is a key mediator of tissue homeostasis through induction of an immune-surveillance phenotype and anti-proliferative environment, thereby acting to restrict neoplastic growth.