Associations between DNA Damage and PD-L1 Expression in Ovarian Cancer, a Potential Biomarker for Clinical Response

Abstract

Programmed death ligand-1 (PD-L1) inhibitors are currently under investigation as a potential treatment option for ovarian cancer. Although this therapy has shown promise, its efficacy is highly variable among patients. Evidence suggests that genomic instability influences the expression of PD-L1, but little is known about this relationship in ovarian cancer. To examine the relationship between PD-L1 expression and genomic instability, we measured DNA damage using Repair Assisted Damage Detection (RADD). We then correlated the presence of persistent DNA damage in the ovarian tumor with protein expression of PD-L1 using immunohistochemistry. Ovarian tumors showed a high prevalence of oxidative DNA damage. As the level of oxidative DNA damage increased, we saw a significant correlation with PD-L1 expression. The highest correlation between DNA damage and PD-L1 expression was observed for mucinous ovarian tumors (r = 0.82), but a strong correlation was also observed for high grade serous and endometrioid tumors (r = 0.67 and 0.69, respectively). These findings link genomic instability to PD-L1 protein expression in ovarian cancer and suggest that persistent DNA damage can be used as a potential biomarker for patient selection for immunotherapy treatment.

The Protein Landscape of Mucinous Ovarian Cancer: Towards a Theranostic

“…PD-L1 may be an inappropriate target for theranostics, although this study raises the question of whether MOC could be targeted by immune checkpoint inhibitors. However, the effectiveness of PD-1/PD-L1 blockade in ovarian cancer has seen limited success and is highly variable between patients and histotypes—the cause of this variability is poorly understood, but is perhaps linked to the degree of genomic instability [ 99 ].…”

Repair-Assisted Damage Detection Reveals Biological Disparities in Prostate Cancer between African Americans and European Americans

“…Therefore, to understand the DNA repair landscape within tumors, a measurement of DNA lesion content is needed to identify where lesion removal and repair processes have failed. We developed the Repair Assisted Damage Detection (RADD) assay to measure total DNA damage and identify specific classes of DNA lesions within tissues [ 14 , 15 , 16 , 17 , 18 ]. RADD harnesses the specificity of DNA repair enzymes to detect and excise DNA damage then tags those sites with a fluorescent dye to quantify damage within a single nucleus [ 14 , 15 , 19 ].…”

“…RADD harnesses the specificity of DNA repair enzymes to detect and excise DNA damage then tags those sites with a fluorescent dye to quantify damage within a single nucleus [ 14 , 15 , 19 ]. RADD can measure DNA repair defects or indicate highly functional DNA repair in tissues [ 15 , 16 ]. Measuring proficiency or deficiency in the DNA repair pathways is a significant enhancement over gene expression signatures and somatic mutation analysis.…”