IgG4 subclass antibodies impair antitumor immunity in melanoma
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, 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
Abstract
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.
Figures
![Figure 1. B cells (CD22 + )…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f1.jpg)
![Figure 2. B cells in melanoma lesions…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f2.jpg)
![Figure 3. Ex vivo stimulation assays demonstrate…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f3.jpg)
![Figure 4. Biological properties of engineered IgG1…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f4.jpg)
![Figure 5. IgG4 irrespective of tumor specificity…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f5.jpg)
![Figure 6. IgG4 blocks IgG1 antibody-dependent tumor…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f6.jpg)
![Figure 7. IgG4 has no antitumoral effector…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f7.jpg)
![Figure 8. Elevated levels of IgG4 antibodies…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3613918/bin/JCI65579.f8.jpg)
Source: PubMed