Abstract B65: IgG4 subclass antibodies impair antitumor immunity in melanoma

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10-driven Th2 type immune responses in a range of inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. We found that CD22+ B cells and IgG4+ infiltrating cells accumulated in melanoma lesions. When compared to B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Consistent with modified Th2-biased inflammation and in situ production of IgG4, we detected IL-10 and IL-4 cytokine mRNA in melanoma lesions. Tumor cells enhanced IL-10, IL-4 and VEGF secretion and production of IgG4 by B cells ex vivo. Despite accumulation in tumors, and in contrast to IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell-mediated tumor killing in vitro and in vivo. Furthermore, treatment with IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions by blocking of FcgammaRI against tumors, providing a novel perspective on tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches. Citation Format: Panagiotis Karagiannis, Amy E. Gilbert, Debra H. Josephs, Niwa Ali, Tihomir Dodev, Louise Saul, Luke Roberts, Emma Beddowes, Alexander Koers, Silvia Ferreira, Jenny L.C. Geh, Ciaran Healy, Mark Harries, Carl Hobbs, Philip J. Blower, Tracey Mitchell, David Fear, James F. Spicer, Katie E. Lacy, Frank O. Nestle, Sophia N. Karagiannis. IgG4 subclass antibodies impair antitumor immunity in melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B65.