Endothelin receptor B predicts poor prognosis in epithelial ovarian cancer (EOC) and can be inhibited to increase intratumoral T cells and enhance tumor vaccine therapy

Abstract

2524 Background: An inability of T cells to penetrate into tumor islets leads to a poor clinical outcome. We sought to identify tumor endothelial regulators of T cell trafficking. Methods: We used immunohistochemistry-guided laser capture microdissection to isolate and profile of vascular cells from EOC with or without (12 each) intratumoral T cells (ITC). Quantitative PCR (qPCR) and western blot of 60 EOC tumors was used to confirm array results and quantitate expression. Kaplan-Meier curves were generated to estimate survival according to high and low expression of ETRB (as determined by ROC analysis). Cox proportional hazard model was used to estimate the hazard ratio (HR). ETRB peptide antagonist BQ-788 was given QOD for 2 weeks to anti-tumor vaccinated mice with established ovarian tumors. After 8 weeks we used FACS and IHC to assess the presence of tumor-infiltrating T cells. Results: We identified ETRB as upregulated by the tumor vascular cells from tumors lacking ITCs. qPCR showed ETRB mRNA was 5.4 fold increased in ITC(-) vs. ITC(+) tumors. Univariate analyses demonstrated that ETRB expression was an independent prognosticator for both OS and DFS in EOC; the five-year overall survival rate was 70% for low ETRB expression versus <5%for high ETRB expression (p < 0.05, HR 0.35 (95% CI 0.17–0.71)). Bivariate analysis indicated that high ETRB expression predicted suboptimal cytoreduction (p < 0.05). High expression of ETRB strongly correlated with ITC (-). ETRB blockade in a murine tumor vaccine model with peptide BQ-788 restricted tumor growth, reduced ascites, and increased survival compared to control animals. Analysis of BQ-788 treated tumors revealed a 5–15× increase in CD4+ and CD8+ intratumoral T cells. Conclusion: ETRB is an important new biomarker, for EOC patients, that correlates with ITC status and predicts both suboptimal cytoreduction and poor clinical outcome. Antagonism of ETRB in mice can restore an otherwise ineffective anti-tumor immune response. This suggests that ETRB inhibition may be a powerful adjuvant for tumor immunotherapy. No significant financial relationships to disclose.