title: Cytokine profiling of tumor interstitial fluid of the breast and its relationship with lymphocyte infiltration and clinicopathological characteristics.
abstract: The tumor microenvironment is composed of many immune cell subpopulations and is an important factor in the malignant progression of neoplasms, particularly breast cancer (BC). However, the cytokine networks that coordinate various regulatory events within the BC interstitium remain largely uncharacterized. Moreover, the data obtained regarding the origin of cytokine secretions, the levels of secretion associated with tumor development, and the possible clinical relevance of cytokines remain controversial. Therefore, we profiled 27 cytokines in 78 breast tumor interstitial fluid (TIF) samples, 43 normal interstitial fluid (NIF) samples, and 25 matched serum samples obtained from BC patients with Luminex xMAP multiplex technology. Eleven cytokines exhibited significantly higher levels in the TIF samples compared with the NIF samples: interleukin (IL)-7, IL-10, fibroblast growth factor-2, IL-13, interferon (IFN)γ-inducible protein (IP-10), IL-1 receptor antagonist (IL-1RA), platelet-derived growth factor (PDGF)-β, IL-1β, chemokine ligand 5 (RANTES), vascular endothelial growth factor, and IL-12. An immunohistochemical analysis further demonstrated that IL-1RA, IP-10, IL-10, PDGF-β, RANTES, and VEGF are widely expressed by both cancer cells and tumor-infiltrating lymphocytes (TILs), whereas IP-10 and RANTES were preferentially abundant in triple-negative breast cancers (TNBCs) compared to Luminal A subtype cancers. The latter observation corresponds with the high level of TILs in the TNBC samples. IL-1β, IL-7, IL-10, and PDGFβ also exhibited a correlation between the TIF samples and matched sera. In a survival analysis, high levels of IL-5, a hallmark TH2 cytokine, in the TIF samples were associated with a worse prognosis. These findings have important implications for BC immunotherapy research.
authors.affiliation: SciLifeLab, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet , Solna, Stockholm, Sweden.
authors.forename: Jaime A
authors.initials: JA
authors.lastname: Espinoza
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, University of Oslo (UiO), Oslo, Norway.
authors.forename: Shakila
authors.initials: S
authors.lastname: Jabeen
authors.affiliation: Danish Cancer Society Research Center, Computational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry, Copenhagen, Denmark; Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany; Institute of Computational Biology, Helmholtz Zentrum Munich, Munich, Germany.
authors.forename: Richa
authors.initials: R
authors.lastname: Batra
authors.affiliation: Danish Cancer Society Research Center, Computational Biology Laboratory, Unit of Statistics, Bioinformatics and Registry , Copenhagen, Denmark.
authors.forename: Elena
authors.initials: E
authors.lastname: Papaleo
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital , Oslo, Norway.
authors.forename: Vilde
authors.initials: V
authors.lastname: Haakensen
authors.affiliation: Department of Pathology, Center of Diagnostic Investigations, Copenhagen University Hospital , Copenhagen, Denmark.
authors.forename: Vera
authors.initials: V
authors.lastname: Timmermans Wielenga
authors.affiliation: Department of Pathology, Center of Diagnostic Investigations, Copenhagen University Hospital , Copenhagen, Denmark.
authors.forename: Maj-Lis
authors.initials: ML
authors.lastname: Møller Talman
authors.affiliation: Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Brunner
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.affiliation: Danish Cancer Society Research Center, Genome Integrity Unit, Cancer Proteomics Group , Copenhagen, Denmark.
authors.forename: Pavel
authors.initials: P
authors.lastname: Gromov
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, University of Oslo (UiO), Oslo, Norway; Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Åslaug
authors.initials: Å
authors.lastname: Helland
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Center for Breast Cancer Research, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, University of Oslo (UiO), Oslo, Norway.
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
authors.affiliation: Danish Cancer Society Research Center, Genome Integrity Unit, Cancer Proteomics Group , Copenhagen, Denmark.
authors.forename: Irina
authors.initials: I
authors.lastname: Gromova
keywords: Breast cancer; TH2; array; cytokine; growth factor; interleukin; interstitial fluid; tumor-infiltrating lymphocyte