Joseph, Janine M.

AbstractProblemPrevious studies identified circulating CD14+HLA‐DRlo/− 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 studyIncident 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−/lowCD14+CD15− monocytic cells, henceforth termed CD14+HLA‐DRlo/− monocytic cells, prior to and after completion of frontline chemotherapy. Multivariable odds ratios (OR) were used to estimate the association between CD14+HLA‐DRlo/− 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).ResultsPatients with elevated frequencies of circulating CD14+HLA‐DRlo/− 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‐DRlo/−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).ConclusionThese findings support the potential clinical relevance of CD14+HLA‐DRlo/−monocytic cells in EOC for prognosis and may indicate a non‐invasive biomarker to measure disease progression.

Abstract Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive/protumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (P &lt; 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, individual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev; 26(3); 420–4. ©2016 AACR.