title: Angels and demons: Th17 cells represent a beneficial response, while neutrophil IL-17 is associated with poor prognosis in squamous cervical cancer.
abstract: The role of interleukin (IL)-17 in cancer remains controversial. In view of the growing interest in the targeting of IL-17, knowing its cellular sources and clinical implications is crucial. In the present study, we unraveled the phenotype of IL-17 expressing cells in cervical cancer using immunohistochemical double and immunofluorescent triple stainings. In the tumor stroma, IL-17 was found to be predominantly expressed by neutrophils (66%), mast cells (23%), and innate lymphoid cells (8%). Remarkably, T-helper 17 (Th17) cells were a minor IL-17 expressing population (4%). A similar distribution was observed in the tumor epithelium. The Th17 and granulocyte fractions were confirmed in head and neck, ovarian, endometrial, prostate, breast, lung, and colon carcinoma. An above median number of total IL-17 expressing cells was an independent prognostic factor for poor disease-specific survival in early stage disease (p= 0.016). While a high number of neutrophils showed at trend toward poor survival, the lowest quartile of mast cells correlated with poor survival (p= 0.011). IL-17 expressing cells and neutrophils were also correlated with the absence of vaso-invasion (p< 0.01). IL-17 was found to increase cell growth or tightness of cervical cancer cell lines, which may be a mechanism for tumorigenesis in early stage disease. These data suggest that IL-17, primarily expressed by neutrophils, predominantly promotes tumor growth, correlated with poor prognosis in early stage disease. Strikingly, a high number of Th17 cells was an independent prognostic factor for improved survival (p= 0.026), suggesting Th17 cells are part of a tumor suppressing immune response.
authors.affiliation: Department of Pathology Leiden University Medical Center ; Leiden, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Punt
authors.affiliation: Department of Pathology Leiden University Medical Center ; Leiden, The Netherlands.
authors.forename: Gert Jan
authors.initials: GJ
authors.lastname: Fleuren
authors.affiliation: Department of Pathology Leiden University Medical Center ; Leiden, The Netherlands.
authors.forename: Eva
authors.initials: E
authors.lastname: Kritikou
authors.affiliation: Department of Rheumatology and Immunology; Erasmus University Medical Center ; Rotterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
authors.affiliation: Department of Gynecology; Leiden University Medical Center ; Leiden, The Netherlands.
authors.forename: J Baptist
authors.initials: JB
authors.lastname: Trimbos
authors.affiliation: Department of Pathology Leiden University Medical Center ; Leiden, The Netherlands.
authors.forename: Ekaterina S
authors.initials: ES
authors.lastname: Jordanova
authors.affiliation: Department of Pathology Leiden University Medical Center ; Leiden, The Netherlands.
authors.forename: Arko
authors.initials: A
authors.lastname: Gorter
keywords: 3, 3′-diamino-benzidine-tetrahydrochloride; DAB; FFPE, formalin-fixed, paraffin-embedded; HPF, high-power field; HPV, human papillomavirus; IL-17; MDSCs, myeloid-derived suppressor cells; MPO, myeloperoxidase; TNM, tumor node metastasis stage; Th17; neutrophil; tumor microenvironment; uterine cervical cancer