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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

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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IgG4 isoallotypes could mediate IgG4-induced impairment of antitumor immunity in melanoma

Submitter: Janardan Pandey | pandeyj@musc.edu

Authors: N/A

Medical University of South Carolina

Published June 24, 2013

Tumor cells have evolved numerous sophisticated strategies for evading host immunosurveillance. In April 2013 in the JCI, Karagiannis et al. provided evidence for a novel mechanism of immunoevasion employed by the melanoma tumors (1). Tumor-infiltrating B cells produced IgG4 antibodies in situ and participated in local tumor surveillance, by interfering with antitumor IgG1-mediated cytotoxicity and phagocytosis of tumor cells.

With the exception of IgG4, all other IgG subclasses express subclass-specific, unique GM (γ marker) allotypes (2). IgG4 molecules, on the other hand, express isoallotypes—determinants that behave as alleles in one IgG subclass (allotypes) but are also expressed in all molecules of at least one other subclass (isotype). Two isoallotypic variants of IgG4 have been characterized at γ4 positions 309 and 409. At position 309, leucine is changed to valine (L309/V309) and at 409, arginine is changed to lysine (R409/K409). Of the two isoallotypes, the functional significance of R409/K409 has been established: R409 enables the so-called IgG4 “Fab arm exchange”, while K409 blocks it (3,4).

Virtually all GM allotypes and isoallotypes are expressed in the Fc region of γ chains, making them the most likely candidates in the genome for epistatic interactions with Fcγ receptor (FcγR) genes expressed on effector cells. We have shown that genetically different IgG1 and FcγRIIIa proteins interact and differentially contribute to the magnitude of antibody-dependent cellular cytotoxicity (ADCC) of cancer cells (5). The Fc regions of isoallotypically different IgG4 molecules may have differential affinity to FcγRI on monocytes, which would result in competitive blockade of antitumor IgG1-mediated ADCC of melanoma cells reported by Karagiannis et al. (1). Similar differential Fcγ4-FcγR interactions could also contribute to the interindividual variability in the therapeutic responses to the chimeric anti-GD2 IgG1 antibody (hu14.18) in patients with melanoma (6).

The tumor escape mechanism identified by Karagiannis et al. (1) is reminiscent of an immunoevasion strategy of herpes simplex virus type 1 and human cytomegalovirus (7,8), with the difference that melanoma tumors produce IgG4 antibodies to compete with antitumor IgG1 antibodies for FcγR binding, while the herpesviruses produce FcγR-like proteins that compete with the cellular FcγRs for the antiviral IgG antibodies. Both mechanisms result in the evasion of host immunosurveillance by blocking the Fc-mediated effector functions. Interestingly, viral FcγRs also have differential affinity to allotypically different IgG proteins (9,10).

References

  1. Karagiannis P, et al. IgG4 subclass antibodies impair antitumor immunity in melanoma. J Clin Invest. 2013;123:1457-1474.
  2. Lefranc MP, Lefranc G. Human Gm, Km, and Am allotypes and their molecular characterization: a remarkable demonstration of polymorphism. Methods Mol Biol. 2012;882:635-680.
  3. Brusco A, et al. Molecular characterization of immunoglobulin G4 gene isoallotypes. Eur J Immunogenet. 1998;25:349-355.
  4. Labrijn AF, et al. Species-specific determinants in the IgG CH3 domain enable Fab-arm exchange by affecting the noncovalent CH3-CH3 interaction strength. J Immunol. 2011;187:3238-3246.
  5. Namboodiri AM, Pandey JP. Differential inhibition of trastuzumab and cetuximab induced cytotoxicity of cancer cells by IgG1 expressing different GM allotypes. Clin Exp Immunol. 2011;166:361-365.
  6. Albertini MR, et al. Phase II trial of hu14.18-IL2 for patients with metastatic melanoma. Cancer Immunol Immunother. 2012;61:2261-2271.
  7. Dubin G, et al. Herpes simplex virus type 1 Fc receptor protects infected cells from antibody-dependent cellular cytotoxicity. J Virol. 1991;65:7046-7050.
  8. Atalay R, et al. Identification and expression of human cytomegalovirus transcription units coding for two distinct Fcgamma receptor homologs. J Virol. 2002;76:8596-8608.
  9. Atherton AK, et al. The herpes simplex virus type 1 Fc receptor discriminates between IgG1 allotypes. Eur J Immunol. 2000;30:2540-2547.
  10. Namboodiri AM, Pandey JP. The human cytomegalovirus TRL11/IRL11-encoded FcγR binds differentially to allelic variants of immunoglobulin G1. Arch Virol. 2011;156:907-910.

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