Trichomonas vaginalis-induced inflammation drives prostate cancer progression via Th17 differentiation and tumor-intrinsic IL-17R signaling

Chronic inflammation, particularly from infections, is increasingly recognized as a driver of prostate cancer (PCa) progression. While Trichomonas vaginalis (Tv), the most common nonviral sexually transmitted parasite, has been linked to prostatic inflammation and elevated PCa risk, the precise immunological mechanisms remain unclear. Current understanding lacks how Tv-induced inflammation specifically influences tumor development, especially regarding T-cell differentiation and direct tumor signaling. This study aimed to elucidate whether Tv-induced epithelial inflammation promotes Th17 differentiation and drives PCa progression through intratumoral IL-17 receptor (IL-17R) signaling.

Researchers investigated the inflammatory mechanisms of Tv in prostate cancer progression using both in vitro and in vivo models. Prostate epithelial cells (RWPE-1 cell line) were infected with Tv to prepare conditioned media (TCM). Human CD4+ T cells were isolated from peripheral blood and incubated with either control conditioned media (CM) or TCM to generate T-CM and T-TCM. The effects of these media on Th17 differentiation, prostate cell proliferation, and migration were assessed. A syngeneic mouse prostate cancer model in C57BL/6 mice was used to evaluate the impact of IL-17R neutralization on tumor growth. Spatial transcriptomic analysis was performed on Tv-treated tumors, and human prostate adenocarcinoma datasets were analyzed for IL17RA expression.

Conditioned media from Tv-stimulated prostate epithelial cells robustly induced IL-6 and IL-1β production. This cytokine milieu promoted IL-6/IL-1R-dependent differentiation of human CD4⁺ T cells into Th17 cells. Conditioned media from these differentiated Th17 cells significantly enhanced the proliferation and migration of both prostate epithelial and cancer cells. Mechanistically, this effect was linked to the activation of IL-17R-TRAF6-NF-κB signaling pathways within the prostate cells. In a syngeneic mouse model, IL-17R neutralization significantly reduced tumor growth, notably without affecting Th17 cell abundance, indicating a direct tumor-intrinsic role for IL-17R signaling.

Spatial transcriptomic analysis of Tv-treated tumors revealed a strong enrichment of IL-17R-associated proliferative and invasive gene programs. Consistent with these preclinical findings, analysis of human prostate adenocarcinoma datasets showed that IL17RA expression was associated with proliferative and invasive signatures and correlated with poorer clinical outcomes.