Details

Autor(en) / Beteiligte

• 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

Titel

IgG4 subclass antibodies impair antitumor immunity in melanoma

Ist Teil von

• The Journal of clinical investigation, 2013-04, Vol.123 (4), p.1457-1474

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.