Document Detail

IgG4 subclass antibodies impair antitumor immunity in melanoma.
MedLine Citation:
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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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-09     Completed Date:  2013-05-20     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1457-74     Citation Subset:  AIM; IM    
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MeSH Terms
Aged, 80 and over
Antibody-Dependent Cell Cytotoxicity
Antineoplastic Agents / pharmacology*
B-Lymphocytes / immunology,  metabolism,  secretion
Cell Polarity
Coculture Techniques
Forkhead Transcription Factors / metabolism
Immunoglobulin G / biosynthesis,  blood,  physiology*
Interleukin-10 / metabolism,  physiology,  secretion
Interleukin-4 / metabolism
Kaplan-Meier Estimate
Lymphatic Metastasis
Melanoma / blood,  immunology*,  mortality,  secondary
Middle Aged
Receptors, IgG / metabolism
Sialic Acid Binding Ig-like Lectin 2 / metabolism
Skin Neoplasms / blood,  immunology*,  mortality,  pathology
Th2 Cells / immunology
Tumor Cells, Cultured
Tumor Escape
Vascular Endothelial Growth Factor A / metabolism
Xenograft Model Antitumor Assays
Grant Support
BB/H019634/1//Biotechnology and Biological Sciences Research Council; C1519/A10331//Cancer Research UK; C16736/A8371//Cancer Research UK; C30122/A11527//Cancer Research UK; MR/J006742/1//Medical Research Council; //Medical Research Council
Reg. No./Substance:
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

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