title: IgG4 subclass antibodies impair antitumor immunity in melanoma.
abstract: Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4(+)-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.
authors: National Institute for Health Research Biomedical Research Centre at Guy's and St. Thomas' Hospitals and King's College London, Cutaneous Medicine and Immunotherapy Unit, St. John's Institute of Dermatology, Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, United Kingdom.
authors: Panagiotis
authors: P
authors: Karagiannis
authors: Amy E
authors: AE
authors: Gilbert
authors: Debra H
authors: DH
authors: Josephs
authors: Niwa
authors: N
authors: Ali
authors: Tihomir
authors: T
authors: Dodev
authors: Louise
authors: L
authors: Saul
authors: Isabel
authors: I
authors: Correa
authors: Luke
authors: L
authors: Roberts
authors: Emma
authors: E
authors: Beddowes
authors: Alexander
authors: A
authors: Koers
authors: Carl
authors: C
authors: Hobbs
authors: Silvia
authors: S
authors: Ferreira
authors: Jenny L C
authors: JL
authors: Geh
authors: Ciaran
authors: C
authors: Healy
authors: Mark
authors: M
authors: Harries
authors: Katharine M
authors: KM
authors: Acland
authors: Philip J
authors: PJ
authors: Blower
authors: Tracey
authors: T
authors: Mitchell
authors: David J
authors: DJ
authors: Fear
authors: James F
authors: JF
authors: Spicer
authors: Katie E
authors: KE
authors: Lacy
authors: Frank O
authors: FO
authors: Nestle
authors: Sophia N
authors: SN
authors: Karagiannis
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016764:Cell Polarity; D018920:Coculture Techniques; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D016753:Interleukin-10 / Q000378:metabolism / Q000502:physiology; D015847:Interleukin-4 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000556:secondary; D051379:Mice; D008875:Middle Aged; D017452:Receptors, IgG / Q000378:metabolism; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000378:metabolism; D012878:Skin Neoplasms / Q000097:blood / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497867:CD22 protein, human; C489017:FCGR1A protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508598:IL4 protein, human; D007074:Immunoglobulin G; D017452:Receptors, IgG; D051918:Sialic Acid Binding Ig-like Lectin 2; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D015847:Interleukin-4