Downregulation of E-selectin and contributions to immune restraining in prostate cancer.
Abstract
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.
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (11)
Ida Deichaite
University of California, San Diego, La Jolla, CA
Andrew Elliott
Ahmed Shabaik
Leisa Sutton
University of California, San Diego, La Jolla, CA
Stephanie Weaver
Fred Hutchinson Cancer Center, Seattle, WA
Miki Haraguchi
Fred Hutchinson Cancer Center, Seattle, WA
Daniel M. Geynisman
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
Shuanzeng Wei
Fox Chase Cancer Center, Philadelphia, PA
Napoleone Ferrara
Department of Pathology, University of California San Diego
Fotis Asimakopoulos
University of California, San Diego, La Jolla, CA
Pablo Tamayo