|IgG4 subclass antibodies impair antitumor immunity in melanoma.|
|PMID: 23454746 Owner: NLM Status: MEDLINE|
|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.|
|Panagiotis Karagiannis; Amy E Gilbert; Debra H Josephs; Niwa Ali; Tihomir Dodev; Louise Saul; Isabel Correa; Luke Roberts; Emma Beddowes; Alexander Koers; Carl Hobbs; Silvia Ferreira; Jenny L C Geh; Ciaran Healy; Mark Harries; Katharine M Acland; Philip J Blower; Tracey Mitchell; David J Fear; James F Spicer; Katie E Lacy; Frank O Nestle; Sophia N Karagiannis|
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|Type: Journal Article; Research Support, Non-U.S. Gov't|
|Title: The Journal of clinical investigation Volume: 123 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2013 Apr|
|Created Date: 2013-05-09 Completed Date: 2013-05-20 Revised Date: 2013-07-11|
Medline Journal Info:
|Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States|
|Languages: eng Pagination: 1457-74 Citation Subset: AIM; IM|
|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.|
|APA/MLA Format Download EndNote Download BibTex|
Aged, 80 and over
Antibody-Dependent Cell Cytotoxicity
Antineoplastic Agents / pharmacology*
B-Lymphocytes / immunology, metabolism, secretion
Forkhead Transcription Factors / metabolism
Immunoglobulin G / biosynthesis, blood, physiology*
Interleukin-10 / metabolism, physiology, secretion
Interleukin-4 / metabolism
Melanoma / blood, immunology*, mortality, secondary
Receptors, IgG / metabolism
Sialic Acid Binding Ig-like Lectin 2 / metabolism
Skin Neoplasms / blood, immunology*, mortality, pathology
Th2 Cells / immunology
Tumor Cells, Cultured
Vascular Endothelial Growth Factor A / metabolism
Xenograft Model Antitumor Assays
|BB/H019634/1//Biotechnology and Biological Sciences Research Council; C1519/A10331//Cancer Research UK; C16736/A8371//Cancer Research UK; C30122/A11527//Cancer Research UK; //Medical Research Council|
|0/Antineoplastic Agents; 0/CD22 protein, human; 0/FCGR1A protein, human; 0/FOXP3 protein, human; 0/Forkhead Transcription Factors; 0/IL10 protein, human; 0/IL4 protein, human; 0/Immunoglobulin G; 0/Receptors, IgG; 0/Sialic Acid Binding Ig-like Lectin 2; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; 130068-27-8/Interleukin-10; 207137-56-2/Interleukin-4|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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