IgG4 subclass antibodies impair antitumor immunity in melanoma

• Published in: The Journal of clinical investigation 2013-04, Vol.123 (4), p.1457-1474
• Main Authors: Karagiannis, Panagiotis, Gilbert, Amy E, Josephs, Debra H, Ali, Niwa, Dodev, Tihomir, Saul, Louise, Correa, Isabel, Roberts, Luke, Beddowes, Emma, Koers, Alexander, Hobbs, Carl, Ferreira, Silvia, Geh, Jenny L C, Healy, Ciaran, Harries, Mark, Acland, Katharine M, Blower, Philip J, Mitchell, Tracey, Fear, David J, Spicer, James F, Lacy, Katie E, Nestle, Frank O, Karagiannis, Sophia N
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Allergens; Allergies; Animals; Antibodies; Antibody-Dependent Cell Cytotoxicity; Antigens; Antineoplastic Agents - pharmacology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomedical research; Cell Polarity; Coculture Techniques; Cytokines; Female; Forkhead Transcription Factors - metabolism; Health aspects; Humans; Immunity; Immunoglobulin G; Immunoglobulin G - biosynthesis; Immunoglobulin G - blood; Immunoglobulin G - physiology; Immunotherapy; Inflammation; Interleukin-10 - metabolism; Interleukin-10 - physiology; Interleukin-4 - metabolism; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Melanoma; Melanoma - blood; Melanoma - immunology; Melanoma - mortality; Melanoma - secondary; Metastasis; Mice; Middle Aged; Patients; Receptors, IgG - metabolism; Sialic Acid Binding Ig-like Lectin 2 - metabolism; Skin cancer; Skin Neoplasms - blood; Skin Neoplasms - immunology; Skin Neoplasms - mortality; Skin Neoplasms - pathology; Th2 Cells - immunology; Tumor Cells, Cultured; Tumor Escape; Tumors; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI65579

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.