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IgG4 subclass antibodies impair antitumor immunity in melanoma
Panagiotis Karagiannis, … , Frank O. Nestle, Sophia N. Karagiannis
Panagiotis Karagiannis, … , Frank O. Nestle, Sophia N. Karagiannis
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1457-1474. https://doi.org/10.1172/JCI65579.
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Research Article Oncology

IgG4 subclass antibodies impair antitumor immunity in melanoma

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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.

Authors

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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Figure 1

B cells (CD22+) infiltrate melanoma lesions and produce IgG.

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B cells (CD22+) infiltrate melanoma lesions and produce IgG.
 
(A) Immun...
(A) Immunohistochemistry showing the presence of lymphocytes (CD45+), mature B cells (CD22+), activated lymphocytes (FoxP3+) (alkaline phosphatase [red], hematoxylin [blue]), and colocalization of all 3 within cutaneous metastases (scale bar: 100 μm; original magnification, ×10). CD22+ cells in melanoma are shown at higher magnification (original magnification, ×40). (B) Significantly increased CD22+ B cell infiltration was measured in primary (n = 6) and metastatic (n = 7) melanoma lesions compared with healthy skin (n = 8). HPF, high-powered microscope field. (C) Comparative real-time PCR showed significantly elevated CD22 expression in primary (n = 10) and metastatic (n = 10) melanomas compared with healthy skin (n = 9). (D) Increased expression of mature IgG mRNA in metastatic melanoma lesions (n = 10) compared with primary melanomas (n = 10) and healthy skin (n = 9) measured by comparative real-time PCR analysis. (E) IgG expression (by comparative real-time RT-PCR) is elevated in melanoma lesions of stage IV patients compared with lesions of stage I–III patients. (F) Immunofluorescent evaluations of IgG+ B cells in human metastatic melanoma lesions (CD22+ B cells in red; left) (IgG+ cells in green; middle) and CD22+IgG+ B cell infiltrates (right). Scale bar: 10 μm; original magnification, ×63. (B and E) *P < 0.01, **P < 0.01, ***P < 0.001, Mann-Whitney U test. (C and D) *P < 0.05, **P < 0.01, ***P < 0.001, Kruskal-Wallis 1-way ANOVA with Dunn’s post-hoc test. Horizontal lines in box plots represent the mean, and whiskers indicate minimum and maximum values

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