IgG4 antibodies and cancer-associated inflammation

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Abstract

The role of B cells and antibodies in cancer is insufficiently understood but is receiving increasing attention. We have recently identified IgG4 as an antibody subclass elicited by melanoma-associated interleukin-10-driven inflammation. In this setting, IgG4 exhibit inefficient immunostimulatory capacity and block the cytotoxic activities of other antibodies. These previously unappreciated mechanisms of immune escape may constitute promising targets for the development of novel anticancer immunotherapies.

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IgG4 subclass antibodies impair antitumor immunity in melanoma.

K Lacy, K Acland, P Blower … (2013)

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.

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The high-affinity human IgG receptor FcγRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy.

Friederike Jönsson, Marc Daëron, Patrick England … (2013)

Receptors for the Fc portion of IgG (FcγRs) are mandatory for the induction of various IgG-dependent models of autoimmunity, inflammation, anaphylaxis, and cancer immunotherapy. A few FcγRs have the ability to bind monomeric IgG: high-affinity mouse mFcγRI, mFcγRIV, and human hFcγRI. All others bind IgG only when aggregated in complexes or bound to cells or surfaces: low-affinity mouse mFcγRIIB and mFcγRIII and human hFcγRIIA/B/C and hFcγRIIIA/B. Although it has been proposed that high-affinity FcγRs are occupied by circulating IgG, multiple roles for mFcγRI and mFcγRIV have been reported in vivo. However, the potential roles of hFcγRI that is expressed on monocytes, macrophages, and neutrophils have not been reported. In the present study, we therefore investigated the role of hFcγRI in antibody-mediated models of disease and therapy by generating hFcγRI-transgenic mice deficient for multiple endogenous FcRs. hFcγRI was sufficient to trigger autoimmune arthritis and thrombocytopenia, immune complex-induced airway inflammation, and active and passive systemic anaphylaxis. We found monocyte/macrophages to be responsible for thrombocytopenia, neutrophils to be responsible for systemic anaphylaxis, and both cell types to be responsible for arthritis induction. Finally, hFcγRI was capable of mediating antibody-induced immunotherapy of metastatic melanoma. Our results unravel novel capabilities of human FcγRI that confirm the role of high-affinity IgG receptors in vivo.

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Monitoring the Systemic Human Memory B Cell Compartment of Melanoma Patients for Anti-Tumor IgG Antibodies

Amy Gilbert, Panagiotis Karagiannis, Tihomir Dodev … (2011)

Melanoma, a potentially lethal skin cancer, is widely thought to be immunogenic in nature. While there has been much focus on T cell-mediated immune responses, limited knowledge exists on the role of mature B cells. We describe an approach, including a cell-based ELISA, to evaluate mature IgG antibody responses to melanoma from human peripheral blood B cells. We observed a significant increase in antibody responses from melanoma patients (n = 10) to primary and metastatic melanoma cells compared to healthy volunteers (n = 10) (P<0.0001). Interestingly, we detected a significant reduction in antibody responses to melanoma with advancing disease stage in our patient cohort (n = 21) (P<0.0001). Overall, 28% of melanoma patient-derived B cell cultures (n = 1,800) compared to 2% of cultures from healthy controls (n = 600) produced antibodies that recognized melanoma cells. Lastly, a patient-derived melanoma-specific monoclonal antibody was selected for further study. This antibody effectively killed melanoma cells in vitro via antibody-mediated cellular cytotoxicity. These data demonstrate the presence of a mature systemic B cell response in melanoma patients, which is reduced with disease progression, adding to previous reports of tumor-reactive antibodies in patient sera, and suggesting the merit of future work to elucidate the clinical relevance of activating humoral immune responses to cancer.

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Author and article information

Journal

Journal ID (nlm-ta): Oncoimmunology

Journal ID (iso-abbrev): Oncoimmunology

Journal ID (publisher-id): ONCI

Title: Oncoimmunology

Publisher: Landes Bioscience

ISSN (Print): 2162-4011

ISSN (Electronic): 2162-402X

Publication date (Print): 01 July 2013

Publication date (Electronic): 07 May 2013

Publication date PMC-release: 07 May 2013

Volume: 2

Issue: 7

Electronic Location Identifier: e24889

Affiliations

Cutaneous Medicine and Immunotherapy Unit; St. John’s Institute of Dermatology; Division of Genetics and Molecular Medicine & NIHR Biomedical Research Centre at Guy’s and St. Thomas’s Hospitals and King’s College London; London, UK

Author notes

[* ]Correspondence to: Sophia N Karagiannis, Email: sophia.karagiannis@ 123456kcl.ac.uk

Article

Publisher ID: 2013ONCOIMM0107 Publisher Item ID: 24889

DOI: 10.4161/onci.24889

PMC ID: 3782134

PubMed ID: 24073371

SO-VID: 16a82427-9b7b-43c5-8344-cece6f73d73f

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This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.

IgG4 antibodies and cancer-associated inflammation : Insights into a novel mechanism of immune escape

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Most cited references 5

IgG4 subclass antibodies impair antitumor immunity in melanoma.

The high-affinity human IgG receptor FcγRI (CD64) promotes IgG-mediated inflammation, anaphylaxis, and antitumor immunotherapy.

Monitoring the Systemic Human Memory B Cell Compartment of Melanoma Patients for Anti-Tumor IgG Antibodies

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