title: Plasma endothelial protein C receptor influences innate immune response in ovarian cancer by decreasing the population of natural killer and TH17 helper cells.
abstract: In spite of the growing importance of endothelial protein C receptor/active protein C (EPCR/aPC) in tumor biology, their impact on immunological homeostasis remains largely unexplored. The objective of this study was to assess whether soluble plasma endothelial protein C receptor (sEPCR), which is a regulator of circulating aPC, is involved in innate immune response in cancer patients. In the Ovcar-3 ovarian cancer line, the role of aPC in secretion of cytokines was analyzed. In parallel, in 33 patients, with a diagnosis of ovarian epithelial cancer, sEPCR was quantified, blood immune cell phenotypes were determined by flow cytometry and plasma cytokines were evaluated using a protein array. Spearman's rank correlation coefficients (r) and coefficient significance was determined by a statistical hypothesis test (α=0.05). Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100 ± 28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥ 0.60); and iv) high levels of sEPCR correlate with high levels of plasma bioactive proteins such as insulin-like growth factor-2 (IGFII), IL-13rα, macrophage inflammatory protein (MIP1α) and matrix metalloproteinase-7 (MMP-7) that have already been proposed as biomarkers for ovarian cancer and particularly those with poor prognosis. In conclusion, sEPCR produced by ovarian cancer cells, by modulating circulating aPC, influences the secretory behavior of tumor cells (cytokines and interleukins). Consequently, sEPCR in turn acts on the innate immune response by decreasing effector cells such as natural killer and T helper cells (TH2, TH17 and TH21).
authors.affiliation: National Institut for Medical Research (INSERM), Cordeliers Research Center (UMRS 872), University of Pierre and Marie Curie and University of Paris Descartes, Paris, France.
authors.forename: Dalel
authors.initials: D
authors.lastname: Azzazene
authors.forename: Hamda
authors.initials: H
authors.lastname: Al Thawadi
authors.forename: Halema
authors.initials: H
authors.lastname: Al Farsi
authors.forename: Samaher
authors.initials: S
authors.lastname: Besbes
authors.forename: Caroline
authors.initials: C
authors.lastname: Geyl
authors.forename: Shahsoltan
authors.initials: S
authors.lastname: Mirshahi
authors.forename: Julia
authors.initials: J
authors.lastname: Pardo
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Faussat
authors.forename: Soria
authors.initials: S
authors.lastname: Jeannette
authors.forename: Amu
authors.initials: A
authors.lastname: Therwath
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
authors.forename: Massoud
authors.initials: M
authors.lastname: Mirshahi
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D045744:Cell Line, Tumor; D000074283:Endothelial Protein C Receptor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D007378:Interleukins / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D020783:Matrix Metalloproteinase 7 / Q000097:blood; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011486:Protein C / Q000096:biosynthesis* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; D007376:Interleukin-2; D007378:Interleukins; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface; D016753:Interleukin-10; D020783:Matrix Metalloproteinase 7; D000098546:Interleukin-21