IgG4 subclass antibodies impair antitumor immunity in melanoma

J Clin Invest. 2013 Apr;123(4):1457-74. doi: 10.1172/JCI65579.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antibody-Dependent Cell Cytotoxicity
  • Antineoplastic Agents / pharmacology*
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Cell Polarity
  • Coculture Techniques
  • Female
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Immunoglobulin G / biosynthesis
  • Immunoglobulin G / blood
  • Immunoglobulin G / physiology*
  • Interleukin-10 / metabolism
  • Interleukin-10 / physiology
  • Interleukin-4 / metabolism
  • Kaplan-Meier Estimate
  • Lymphatic Metastasis
  • Male
  • Melanoma / blood
  • Melanoma / immunology*
  • Melanoma / mortality
  • Melanoma / secondary
  • Mice
  • Middle Aged
  • Receptors, IgG / metabolism
  • Sialic Acid Binding Ig-like Lectin 2 / metabolism
  • Skin Neoplasms / blood
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / mortality
  • Skin Neoplasms / pathology
  • Th2 Cells / immunology
  • Tumor Cells, Cultured
  • Tumor Escape
  • Vascular Endothelial Growth Factor A / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • CD22 protein, human
  • FCGR1A protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL10 protein, human
  • IL4 protein, human
  • Immunoglobulin G
  • Receptors, IgG
  • Sialic Acid Binding Ig-like Lectin 2
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Interleukin-10
  • Interleukin-4