Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Batman S

PROVIDER: S-EPMC8073346 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Ovarian cancer (OC) is one of the deadliest gynecological cancers. Recent studies suggest a crucial role of inflammatory immune system cells in the progression and metastasis of OC. The understanding of inflammatory mechanisms is pivotal for the selection of a biomarker that allows the differentiation between malignant and benign tumors, monitoring the progression of the disease, and identification of patients that will respond to implemented treatment. Our study is aimed at evaluating the profile of IL-6 in the plasma and peritoneal fluid (PF) of patients with various clinical manifestations of OC (n = 78). We also examined the relationship between IL-6 and PD-L1/PD-L2 positive CD45+CD14+ inflammatory cell (MO/MA) levels in three OC environments (TME): peripheral blood (PB), PF, and tumor (TT) and their clinical and prognostic relevance in OC patients. The expression of PD-L1/PD-L2 molecules was analyzed by flow cytometry. The IL-6 levels were determined by ELISA. We found an elevated level of PD-L1/PD-L2 positive MO/MA in TT compared to PB (p < 0.0001). Significantly higher (p < 0.0001) levels of IL-6 were observed in PF of the OC patients than in the benign ovarian tumor group (n = 31). Additionally, we found higher IL-6 levels in PF than in the plasma of the OC patients. Interestingly, accumulation of IL-6 was observed in PF of patients with low-differentiated OC and correlated with worse prognosis. Moreover, we observed correlations between the level of IL-6 and CD45+CD14+ cells and between CD45+CD14+PD-L1+ cells and the IL-6 level in PF. For the first time, we discovered that the higher percentage of CD45+CD14+PD-L2+ cells in PF predicts better survival of OC patients. Our study suggests that CD45+CD14+PD-L2+ cells and IL-6 may be predictive biomarkers for OC patients. Understanding how the composition of TME changes during OC development and progression is a prerequisite for projecting new therapeutic strategies. Overall, further validation research is warranted.