title: Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer.
abstract: An increased level of interleukin-6 (IL-6) in epithelial ovarian cancer (EOC) is correlated with a worse prognosis. IL-6 stimulates tumor-growth and inflammation. We investigated the intricate interaction between the IL-6 signaling pathway and tumor-infiltrating myeloid cells (TIMs) to determine their prognostic impact in EOC. 160 EOC samples were analyzed for the expression of IL-6, its receptor (IL-6R) and downstream signaling via pSTAT3 by immunohistochemistry. Triple color immunofluorescence confocal microscopy was used to identify myeloid cell populations by CD14, CD33, and CD163. The relationship between these markers, tumor-infiltrating immune cells, clinical-pathological characteristics and survival was investigated. EOC displayed a dense infiltration with myeloid cells, in particular of the CD163+type. The distribution pattern of all myeloid subtypes was comparable among the different histological subtypes. Analysis of the tumor cells revealed a high expression of IL-6R in 15% and of IL-6 in 23% of patients. Interestingly, tumors expressing IL-6 or IL-6R formed two different groups. Tumors with a high expression of IL-6R displayed low mature myeloid cell infiltration and a longer disease-specific survival (DSS), especially in late stage tumors. High expression of IL-6R was an independent prognostic factor for survival by multivariate analyses (hazard ratio = 0.474,p= 0.011). In contrast, tumors with high epithelial IL-6 expression displayed a dense infiltration of mature myeloid cells and were correlated with a shorter DSS. Furthermore, in densely CD8+T-cell infiltrated tumors, the ratio between these lymphoid cells and CD163+myeloid cells was predictive for survival. Thus, IL-6 and IL-6R are opposite markers for myeloid cell infiltration and survival.
authors.affiliation: Department of Gynecologic Oncology; University of Groningen; University Medical Center Groningen ; Hanzeplein ; Groningen, The Netherlands ; Department of Medical Microbiology; University of Groningen; University Medical Center Groningen ; Hanzeplein , Groningen, The Netherlands.
authors.forename: McA
authors.initials: M
authors.lastname: Wouters
authors.affiliation: Department of ClinicalOncology; Leiden University Medical Center ; Albinusdreef , Leiden, The Netherlands.
authors.forename: E M
authors.initials: EM
authors.lastname: Dijkgraaf
authors.affiliation: Department of Biostatistics and Computational Biology; Dana-Farber Cancer Institute ; Boston, MA USA ; Department of Biostatistics; Harvard School of Public Health ; Boston, MA USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Kuijjer
authors.affiliation: Center for Gynaecological Oncology Amsterdam ; VUMC, De Boelelaan , Amsterdam, The Netherlands.
authors.forename: E S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Pathology; University of Groningen; University Medical Center Groningen ; Hanzeplein , Groningen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Hollema
authors.affiliation: Department of ClinicalOncology; Leiden University Medical Center ; Albinusdreef , Leiden, The Netherlands.
authors.forename: Mjp
authors.initials: M
authors.lastname: Welters
authors.affiliation: Department of ClinicalOncology; Leiden University Medical Center ; Albinusdreef , Leiden, The Netherlands.
authors.forename: Jjm
authors.initials: J
authors.lastname: van der Hoeven
authors.affiliation: Department of Medical Microbiology; University of Groningen; University Medical Center Groningen ; Hanzeplein , Groningen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Daemen
authors.affiliation: Department of ClinicalOncology; Leiden University Medical Center ; Albinusdreef , Leiden, The Netherlands.
authors.forename: J R
authors.initials: JR
authors.lastname: Kroep
authors.affiliation: Department of Gynecologic Oncology; University of Groningen; University Medical Center Groningen ; Hanzeplein ; Groningen, The Netherlands.
authors.forename: H W
authors.initials: HW
authors.lastname: Nijman
authors.affiliation: Department of ClinicalOncology; Leiden University Medical Center ; Albinusdreef , Leiden, The Netherlands.
authors.forename: S H
authors.initials: SH
authors.lastname: van der Burg
keywords: DSS, disease-specific survival; EOC, epithelial ovarian cancer; FIGO, International Federation of Gynecology and Obstetrics; IL-6, interleukin-6; IL-6R, interleukin-6 receptor; IL-6R, interleukin-6, IL-6, interleukin-6 receptor; MDSC, myeloid-derived suppressor cell; T reg, regulatory T cell; TAM, tumor-associated macrophage; TIL, tumor-infiltrating lymphocytes; TIM, tumor-infiltrating myeloid cell; TMA, tissue microarray; epithelial ovarian cancer; pSTAT3; pSTAT3, phosphorylated signal transducer and activator of transcription 3; tumor-infiltrating myeloid cells