title: STAT1-associated intratumoural TH1 immunity predicts chemotherapy resistance in high-grade serous ovarian cancer.
abstract: High-grade serous ovarian carcinoma (HGSC) accounts for 70% of all epithelial ovarian cancers but clinical management is challenged by a lack of accurate prognostic and predictive biomarkers of chemotherapy response. This study evaluated the role of Signal Transducer and Activator of Transcription 1 (STAT1) as an independent prognostic and predictive biomarker and its correlation with intratumoural CD8+T cells in a second independent biomarker validation study. Tumour STAT1 expression and intratumoural CD8+T cell infiltration were assessed by immunohistochemistry as a multicentre validation study conducted on 734 chemotherapy-naïve HGSCs. NanoString-based profiling was performed to correlate expression of STAT1 target genesCXCL9, CXCL10andCXCL11withCD8Atranscript expression in 143 primary tumours. Multiplexed cytokine analysis of pre-treatment plasma from resistant and sensitive patients was performed to assess systemic levels of STAT1-induced cytokines. STAT1 was validated as a prognostic and predictive biomarker in both univariate and multivariate models and its expression correlated significantly with intra-epithelial CD8+T cell infiltration in HGSC. STAT1 levels increased the prognostic and predictive value of intratumoural CD8+T cells, confirming their synergistic role as biomarkers in HGSC. In addition, expression of STAT1 target genes (CXCL9, CXCL10andCXCL11) correlated significantly with levels of, andCD8Atranscripts from intratumoural CD8+T cells within the resistant and sensitive tumours. Our findings provide compelling evidence that high levels of STAT1, STAT1-induced chemokines and CD8+T cells correlate with improved chemotherapy response in HGSC. These results identify STAT1 and its target genes as novel biomarkers of chemosensitivity in HGSC. These findings provide new translational opportunities for patient stratification for immunotherapies based on emerging biomarkers of inflammation in HGSC. An improved understanding of the role of interferon-inducible genes will be foundational for developing immunomodulatory therapies in ovarian cancer.
authors.affiliation: Department of Biomedical and Molecular Sciences Queen's University Kingston Ontario K7L 3N6 Canada.
authors.forename: Katrina K
authors.initials: KK
authors.lastname: Au
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal Montreal Quebec H2X 0A9 Canada.
authors.forename: Cécile
authors.initials: C
authors.lastname: Le Page
authors.affiliation: Department of Biomedical and Molecular Sciences Queen's University Kingston Ontario K7L 3N6 Canada.
authors.forename: Runhan
authors.initials: R
authors.lastname: Ren
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal Montreal Quebec H2X 0A9 Canada.
authors.forename: Liliane
authors.initials: L
authors.lastname: Meunier
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal Montreal Quebec H2X 0A9 Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Clément
authors.affiliation: Department of Pathology and Molecular Medicine Kingston General Hospital Kingston Ontario K7L 3N6 Canada.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Tyrishkin
authors.affiliation: Department of Obstetrics and Gynecology Kingston General Hospital Kingston Ontario K7L 3N6 Canada.
authors.forename: Nichole
authors.initials: N
authors.lastname: Peterson
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de Montréal Montreal Quebec H2X 0A9 Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kendall-Dupont
authors.affiliation: Department of Pathology and Molecular Medicine Kingston General Hospital Kingston Ontario K7L 3N6 Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Childs
authors.affiliation: Department of Obstetrics and Gynecology Kingston General Hospital Kingston Ontario K7L 3N6 Canada.
authors.forename: Julie-Ann
authors.initials: JA
authors.lastname: Francis
authors.affiliation: Department of Biomedical and Molecular Sciences Queen's University Kingston Ontario K7L 3N6 Canada.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Graham
authors.affiliation: Department of Biomedical and Molecular SciencesQueen's UniversityKingstonOntarioK7L 3N6Canada; Cancer Biology and Genetics DivisionQueen's Cancer Research Institute, Queen's UniversityOntarioK7L 3N6Canada.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Craig
authors.affiliation: Departments of Genetics and Pathology Faculdade de Medicina de Ribeirão Preto - USP Av. Bandeirantes Ribeirão Preto São Paulo 3900 Brazil.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
authors.affiliation: Centre de recherche du Centre hospitalier de l'Université de Montréal (CRCHUM) and Institut du cancer de MontréalMontrealQuebecH2X 0A9Canada; Department of MedicineUniversité de MontréalMontrealQuebecH3C 3J7Canada.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mes-Masson
authors.affiliation: Department of Biomedical and Molecular SciencesQueen's UniversityKingstonOntarioK7L 3N6Canada; Department of Obstetrics and GynecologyKingston General HospitalKingstonOntarioK7L 3N6Canada; Cancer Biology and Genetics DivisionQueen's Cancer Research Institute, Queen's UniversityOntarioK7L 3N6Canada.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Koti
keywords: STAT1; chemoresistance; interferon; intratumoural CD8+ T cell; ovarian cancer