Downregulation of E-selectin and contributions to immune restraining in prostate cancer.

257 Background: Immune surveillance in prostate cancer (PCa) relies on leukocyte trafficking into target tissues, a process mediated by endothelial adhesion molecules. This study investigates the role of E-selectin (SELE) in PCa immune evasion and patient outcomes. Methods: We analyzed transcriptomic data from 7,523 PCa samples (4,768 localized; 2,755 metastatic) molecularly profiled at Caris Life Sciences to assess SELE expression. Correlations between TNF and adhesion molecule expression were examined in normal prostate and PCa tissues. Survival analysis was performed based on SELE expression levels. Immunohistochemistry was conducted to evaluate SELE protein expression in tumor, benign prostatic hyperplasia (BPH), and stromal samples. Results: SELE was significantly upregulated in localized PCa samples compared to metastases (SELE: 0.83 vs 0.47 TPM, p<0.001), along with SELP (P-selectin) (3.15 vs 1.29 TPM, p<0.0001), ICAM1 (5.05 vs 3.70, P<0.0001) and VCAM1 (7.10 vs 5.41, P<0.001), while TNF expression was similar (0.48 vs 0.43 TPM, P<0.001). TNF positively correlated with SELE, with a stronger correlation observed in metastatic vs localized PCa samples, suggesting altered transcriptional regulation. High expression of SELE was associated with improved survival among patients with localized PCa (HR=0.61, p<0.0001), with no significant difference observed among those with metastatic PCa (HR=0.90, p=0.153). Among those with localized PCa, high expression of SELP was also associated with improved survival (HR=0.75, p<0.001), while worse overall survival was associated with high expression of ICAM1 (HR=1.58, p<0.0001), VCAM1 (HR=1.73, p<0.0001), and TNF (HR=1.23, p=0.004). Combined high SELE/low TNF demonstrated an enhanced survival effect compared to low SELE/high TNF (HR=0.44, p<0.001). Conclusions: Our findings suggest that downregulation of SELE in PCa contributes to tumor "coldness" by potentially reducing anti-tumor immune cell infiltration. This mechanism may explain the limited efficacy of immune checkpoint inhibitors in PCa. The strong association between SELE expression and improved survival highlights their potential for prognostic biomarker and therapeutic target in PCa.