title: CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer.
abstract: Tumour-infiltrating lymphocytes (TILs) are associated with improved survival in several epithelial cancers. The two chemokines CXCL9 and CXCL10 facilitate chemotactic recruitment of TILs, and their intratumoral accumulation is a conceivable way to improve TIL-dependent immune intervention in cancer. However, the prognostic impact of CXCL9 and CXCL10 in high-grade serous ovarian cancer (HGSC) is largely unknown.
  
  
  
  One hundred and eighty four cases of HGSC were immunohistochemically analyzed for CXCL9, CXCL10. TILs were assessed using CD3, CD56 and FOXP3 staining. Chemokine regulation was investigated using the ovarian cancer cell lines OV-MZ-6 and SKOV-3.
  
  
  
  High expression of CXCL9 and CXCL10 was associated with an approximately doubled overall survival (n=70, CXCL9: HR 0.41; P=0.006; CXCL10: HR 0.46; P=0.010) which was confirmed in an independent validation set (n=114; CXCL9: HR 0.60; P=0.019; CXCL10: HR 0.52; P=0.005). Expression of CXCR3 ligands significantly correlated with TILs. In human ovarian cancer cell lines the cyclooxygenase (COX) metabolite Prostaglandin E2 was identified as negative regulator of chemokine secretion, whereas COX inhibition by indomethacin significantly upregulated CXCL9 and CXCL10. In contrast, celecoxib, the only COX inhibitor prospectively evaluated for therapy of ovarian cancer, suppressed NF-κB activation and inhibited chemokine release.
  
  
  
  Our results support the notion that CXCL9 and CXCL10 exert tumour-suppressive function by TIL recruitment in human ovarian cancer. COX inhibition by indomethacin, not by celecoxib, may be a promising approach to concomitantly improve immunotherapies.
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Bronger
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Singer
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Windmüller
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Reuning
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zech
authors.affiliation: Department of Pathology, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Delbridge
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Dorn
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Kiechle
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Schmalfeldt
authors.affiliation: Department of Gynecology and Obstetrics, Klinikum rechts der Isar, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schmitt
authors.affiliation: Department of Pathology, Technical University of Munich, Ismaninger Straße 22, 81675 Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Avril
mesh_terms: D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000502:physiology*; D054370:Chemokine CXCL9 / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008024:Ligands; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D016861:Cyclooxygenase Inhibitors; D008024:Ligands; D007213:Indomethacin