Circulating CD14+ HLA-DRlo/- monocytic cells as a biomarker for epithelial ovarian cancer progression

Abstract

Problem: Previous studies identified circulating CD14⁺ HLA-DR^lo/- monocytic cells as an immune suppressive subset in solid malignancies, such as prostate, renal cell carcinoma, and pancreatic cancer. Such monocytic cells have been implicated not only in tumour progression but also as a potential barrier for immunotherapy. This study examined the relationship between the frequency of circulating monocytic cells and epithelial ovarian cancer (EOC) progression pre- and post-frontline chemotherapy, defined by disease stage, which is a leading prognostic factor for this malignancy.

Method of study: Incident cases of 236 women with EOC were recruited and comprehensive flow cytometry was utilized to assess the frequency of peripheral blood CD33⁺ CD11b⁺ HLA-DR^-/low CD14⁺ CD15^- monocytic cells, henceforth termed CD14⁺ HLA-DR^lo/- monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14⁺ HLA-DR^lo/- monocytic cell percentages and disease stage. Wilcoxon signed-rank tests evaluated changes in these monocytic cell levels pre- and post-chemotherapy in a patient subset (n = 70).

Results: Patients with elevated frequencies of circulating CD14⁺ HLA-DR^lo/- monocytic cells at diagnosis were at 3.33-fold greater odds of having advanced stage (III/IV) EOC (CI: 1.04-10.64), with a significant trend in increasing CD14⁺ HLA-DR^lo/- monocytic cell levels (P = .04). There was a 2.02% median decrease of these monocytic cells post-chemotherapy among a subset of patients with advanced stage disease (P < .0001).

Conclusion: These findings support the potential clinical relevance of CD14⁺ HLA-DR^lo/- monocytic cells in EOC for prognosis and may indicate a non-invasive biomarker to measure disease progression.

Keywords: MDSC; biomarker; monocytes; monocytic cells; ovarian cancer.

Figure 1.

Representative strategy used to identify CD14⁺HLA-DR^lo/- monocytic cell subsets in women with epithelial ovarian cancer. Mononuclear cells were analyzed using a series of sequential regions to exclude debris, apoptotic events, aggregates and CD45 negative events (not shown). Panel 1: A series of regions were created to exclude lineage positive (CD3, CD19, and CD56) cells (R1); Panel 2: CD33 and CD11b dual positive cells (R2); and Panel 3: HLADR negative to dim cells (R3). Panel 4: The CD15 vs. CD14 dotplot gated on R2, R3, and excluding cells in R1 was used to define CD14⁺HLA-DR^lo/- monocytic cells (excludes cells in R4).

Figure 2

CD14+HLA‐DRlo/− monocytic cell levels % gated pre‐ and post‐chemotherapy intervention. Among women with early stage serous EOC, CD14+HLA‐DRlo/− monocytic cell levels decreased from a median of 4.93% cells gated pre‐chemotherapy to 3.57% cells gated post‐chemotherapy (P = .19). Among women with advanced stage serous EOC, CD14+HLA‐DRlo/− monocytic cell levels were found to decrease from a median of 8.45% cells gated pre‐chemotherapy to 4.88% cells gated post‐chemotherapy (P < .0001)