Tumor-infiltrating Cytotoxic T Lymphocytes as Independent Prognostic Factor in Epithelial Ovarian Cancer With Wilms Tumor Protein 1 Overexpression

Abstract

Immune response characterization at the primary tumor site enables the design of therapeutic vaccination strategies with higher efficacy in epithelial ovarian cancer (EOC). In this study, we related Wilms tumor protein 1 (WT1) overexpression, a well-established immunotherapeutic target, to clinicopathological characteristics, immunological parameters, and survival in primary EOC. WT1 overexpression was evaluated in primary EOC tissue of 270 patients by immunohistochemistry on tissue microarrays (TMAs). Clinicopathological characteristics, follow-up, and data on infiltration of CD8(+) cytotoxic T lymphocytes (CTLs), FoxP3(+) regulatory T lymphocytes (Tregs), major histocompatibility complex (MHC) class I, and II molecule expression, were derived from a previously published dataset. WT1 overexpression was defined as positive immunostaining for WT1. WT1 overexpression, present in 56.3% of EOC, was associated with infiltration of Tregs [ odds ratio (OR), 2.7; 95% confidence interval (95% CI), 1.6-4.7; P < 0.001] and up-regulation of MHC class II (OR, 2.2; 95% CI, 1.2-4.1; P = 0.014). Advanced stage (OR, 4.0; 95% CI, 1.9-8.6; P < 0.001) and serous histology (OR, 6.7; 95% CI, 3.2-13.6; P < 0.001) were independent predictors of WT1 overexpressing EOC. High number of CTL was an independent prognostic factor for progression-free survival (hazard ratio, 0.5; 95% CI, 0.3-0.8; P = 0.006) in WT1 overexpressing EOC. As WT1 overexpressing EOC is associated with CTL and Treg infiltration next to MHC class II up-regulation, future clinical trials should evaluate the combination of therapeutic WT1 vaccines with strategies depleting Tregs and/or up-regulating MHC class I, in an attempt to enhance clinical efficacy in EOC patients.