title: Elevated IgG4 in patient circulation is associated with the risk of disease progression in melanoma.
abstract: Emerging evidence suggests pathological and immunoregulatory functions for IgG4 antibodies and IgG4+B cells in inflammatory diseases and malignancies. We previously reported that IgG4 antibodies restrict activation of immune effector cell functions and impair humoral responses in melanoma. Here, we investigate IgG4 as a predictor of risk for disease progression in a study of human sera (n = 271: 167 melanoma patients; 104 healthy volunteers) and peripheral blood B cells (n = 71: 47 melanoma patients; 24 healthy volunteers). IgG4 (IgG4/IgGtotal) serum levels were elevated in melanoma. High relative IgG4 levels negatively correlated with progression-free survival (PFS) and overall survival. In early stage (I-II) disease, serum IgG4 was independently negatively prognostic for progression-free survival, as was elevation of IgG4+circulating B cells (CD45+CD22+CD19+CD3-CD14-). In human tissues (n = 256; 108 cutaneous melanomas; 56 involved lymph nodes; 60 distant metastases; 32 normal skin samples) IgG4+cell infiltrates were found in 42.6% of melanomas, 21.4% of involved lymph nodes and 30% of metastases, suggesting inflammatory conditions that favor IgG4 at the peripheral and local levels. Consistent with emerging evidence for an immunosuppressive role for IgG4, these findings indicate association of elevated IgG4 with disease progression and less favorable clinical outcomes. Characterizing immunoglobulin and other humoral immune profiles in melanoma might identify valuable prognostic tools for patient stratification and in the future lead to more effective treatments less prone to tumor-induced blockade mechanisms.
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK ; University Hospital of Hamburg Eppendorf; Department of Oncology; Hematology and Stem Cell Transplantation ; Hamburg, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Karagiannis
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Federica
authors.initials: F
authors.lastname: Villanova
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK ; Department of Research Oncology; Division of Cancer Studies; Faculty of Life Sciences and Medicine; King's College London; Guy's Hospital ; London, UK.
authors.forename: Debra H
authors.initials: DH
authors.lastname: Josephs
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Isabel
authors.initials: I
authors.lastname: Correa
authors.affiliation: King's College London; Faculty of Life Sciences and Medicine; Division of Cancer Studies; Cancer Epidemiology Group; Guy's Hospital; London, UK.
authors.forename: Mieke
authors.initials: M
authors.lastname: Van Hemelrijck
authors.affiliation: Wolfson Center for Age-Related Diseases; King's College London ; London, UK.
authors.forename: Carl
authors.initials: C
authors.lastname: Hobbs
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK ; Department of Research Oncology; Division of Cancer Studies; Faculty of Life Sciences and Medicine; King's College London; Guy's Hospital ; London, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Saul
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Isioma U
authors.initials: IU
authors.lastname: Egbuniwe
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Isabella
authors.initials: I
authors.lastname: Tosi
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK ; Breakthrough Breast Cancer Research Unit; Department of Research Oncology; Guy's Hospital; King's College London School of Medicine ; London, United Kingdom.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Ilieva
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Kent
authors.affiliation: Skin Tumor Unit; St. John's Institute of Dermatology; Guy's Hospital, King's College London and Guy's and St Thomas' NHS Trust ; London, UK.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Calonje
authors.affiliation: Clinical Oncology; Guy's and St. Thomas's NHS Foundation Trust , London, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Harries
authors.affiliation: Department of Research Oncology; Division of Cancer Studies; Faculty of Life Sciences and Medicine; King's College London; Guy's Hospital ; London, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Fentiman
authors.affiliation: Department of Research Oncology; Division of Cancer Studies; Faculty of Life Sciences and Medicine; King's College London; Guy's Hospital ; London, UK.
authors.forename: Joyce
authors.initials: J
authors.lastname: Taylor-Papadimitriou
authors.affiliation: Department of Research Oncology; Division of Cancer Studies; Faculty of Life Sciences and Medicine; King's College London; Guy's Hospital ; London, UK.
authors.forename: Joy
authors.initials: J
authors.lastname: Burchell
authors.affiliation: Department of Research Oncology; Division of Cancer Studies; Faculty of Life Sciences and Medicine; King's College London; Guy's Hospital ; London, UK.
authors.forename: James F
authors.initials: JF
authors.lastname: Spicer
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK ; Skin Tumor Unit; St. John's Institute of Dermatology; Guy's Hospital, King's College London and Guy's and St Thomas' NHS Trust ; London, UK.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lacy
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Frank O
authors.initials: FO
authors.lastname: Nestle
authors.affiliation: St. John's Institute of Dermatology; Division of Genetics and Molecular Medicine; Faculty of Life Sciences and Medicine; King's College London & NIHR Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London; Guy's Hospital; King's College London ; London, UK.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Karagiannis
keywords: B cells; IgG4; biomarker; cancer inflammation; humoral response; immunomodulation; immunomonitoring; immunosuppression; melanoma; prognosis