The Infiltration of IL-18-Related Immune Cells and Their Bidirectional Regulatory Roles in the Pathogenesis of Prostate Cancer.

Abstract

Background: In recent years, the incidence and mortality of prostate cancer (PCa) have risen significantly, rendering it a serious health concern for middle-aged and elderly men. Interleukin-18 (IL-18), an important pro-inflammatory cytokine within the interleukin-1 superfamily, has been implicated in various malignancies, yet there is a notable scarcity of comprehensive studies exploring the regulatory role of IL-18 in the onset and progression of PCa.

Methods: This study employed integrated bioinformatics and immunohistochemical analyses to investigate the expression patterns and potential mechanistic roles of IL-18 and its receptors in PCa. Differential expression analyses were performed on IL-18 mRNA and protein levels in normal prostate (NP), benign prostatic hyperplasia (BPH), and PCa tissues. Correlations between IL-18 expression and clinical features were also assessed. Additionally, immune cell infiltration was analyzed to explore the immunological landscape associated with IL-18 expression.

Results: A comparative analysis of IL-18 mRNA and protein expression levels between paracancerous and PCa tissues revealed an obvious decrease in IL-18 expression in both benign prostatic hyperplasia (BPH) and PCa tissues compared to normal prostate (NP) tissue (p < 0.05). The expression of IL-18 was found to be significantly elevated in correlation with the progression of pathological T-stage and an increase in the Gleason score among patients with PCa. Immune infiltration analysis, which examined 24 immune cell types, showed that IL-18 was correlated with the infiltration of Th17 cells negatively, while exhibiting positive correlations with other immune cell types. Congo red staining revealed that eosinophils were predominantly localized in the entravascular and perivascular regions of prostate tissues. Notably, Eosinophil infiltration was significantly increased PCa tissues when compared to NP tissues (p < 0.05). Immunohistochemical staining also showed that CD20⁺ B cells were mainly present in perivascular areas, with significantly higher infiltration levels observed in PCa compared to NP and BPH (p < 0.05). Similarly, CD4⁺ T cell infiltration was significantly increased in PCa compared to NP and BPH (p < 0.05). Additionally, the number of mast cell infiltration increased significantly in PCa tissues relative to NP and BPH through Toluidine blue staining (p < 0.05).

Conclusions: IL-18 may play a dual regulatory role in PCa development. In the early stages of the disease, IL-18 may act to inhibit tumorigenesis, whereas, in later stages, it may promote tumor progression in a pro-carcinogenic manner.