Intersection of DNA Repair Pathways and the Immune Landscape Identifies PD-L2 as a Prognostic Marker in Epithelial Ovarian Cancer.

Background: Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. In this study, we explore the association between DNA repair proteins, immune response markers, and clinical outcome in women with EOC.

Methods: Immunohistochemical analysis of TMA with 181 EOC samples was used to determine expression levels for DNA repair proteins (PARP, PTEN, p53, H2Ax, FANCD2, and ATM) and immune-markers (CD4, CD8, CD68, PD-L2, PD-L1, and FOXP3). Biomarker expression was correlated to clinical data. Prognostic discriminatory ability was assessed per the combination of biomarkers.

Results: Tumor immunity biomarkers correlated with HRD biomarkers. High PD-L2 was significantly associated with high expression of CD8 ( = 0.18), CD68 ( = 0.17), and FOXp3 ( = 0.16) (all, < 0.05). In a multivariate analysis, PD-L2 (hazard ratio (HR) 1.89), PARP (HR 1.75), and PTEN (HR 1.96) expressions were independently associated with decreased progression-free survival (PFS), whereas PD-L1 (HR 0.49) and CD4 (HR 0.67) were associated with improved PFS (all, < 0.05). In 15 biomarker combinations, six combinations exhibited a discriminatory ability of >20% for the 4.5-year PFS rate, with four based on PD-L2 (PARP, PTEN, CD4, and PD-L1, 20.5-30.0%).

Conclusions: Increased PD-L2 expression is a prognostic marker of decreased survival in EOC. Interaction between tumor DNA repair and microenvironment determines tumor progression and survival.