Abstract
Simple SummaryHere, we examined the interaction between DNA repair proteins and immune biomarkers and their association with survival in 181 cases of epithelial ovarian carcinoma (EOC). We used a panel of 12 antibodies for immunocytochemistry staining of tissue microarray (TMA) consisting of 181 cases. Applying standard statistical methods, we detected that PD-L2 expression was associated with decreased survival in ovarian cancer. This is the first demonstration that increased expression of PD-L2 may serve as a marker for decreased progression-free survival (PFS). Therefore, further investigation into PD-L2 based immunotherapy as a strategy to treat ovarian cancer is warranted.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 (r = 0.18), CD68 (r = 0.17), and FOXp3 (r = 0.16) (all, p < 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, p < 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.
Highlights
Most women with ovarian cancer present with advanced disease at diagnosis and despite an initial response to treatment, the majority experience recurrence and die of chemoresistant disease
Disruption of the programmed cell death 1 (PD-1) pathway has been shown to enhance tumor immune response [4], suggesting that PD-1/PD-L1 has a role in ovarian cancer treatment
While PD-1 is a transmembrane receptor expressed at the cell surface of T cells, B cells, monocytes, NK cells, and dendritic cells [5], inducible expression of PD-L2 is mainly through Th2-associated cytokines, on the surface of macrophages, dendritic cells, and other immune and non-immune cells [6]
Summary
Most women with ovarian cancer present with advanced disease at diagnosis and despite an initial response to treatment, the majority experience recurrence and die of chemoresistant disease. I.e., the DNA repair pathway and the immune checkpoint pathway, are being vigorously investigated and both are in clinical trials in ovarian and other cancers. Disruption of the PD-1 pathway has been shown to enhance tumor immune response [4], suggesting that PD-1/PD-L1 has a role in ovarian cancer treatment. Targeting DNA repair and immune checkpoint pathways has been the focus of multiple clinical trials. 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). Interaction between tumor DNA repair and microenvironment determines tumor progression and survival
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