Autoantibodies to the NY-ESO-1 Tumor Antigen in Metastatic Melanoma: Sialylation of the Fc Region of Immunoglobulin G Induces Differential Expression Signatures of Inflammatory Molecules During Dendritic Cell Differentiation and Maturation

Abstract

Purpose: We tested the hypothesis that different glycoforms of antibodies from patients with metastatic melanoma have different functional effects on human dendritic cell differentiation and maturation. Methods: Antibodies to the cancer antigen NY-ESO-1 were affinity-purified from patients with melanoma and further fractionated into different glycoforms by lectin chromatography. Sialic acid-rich and sialic acid-poor fractions of these immunoglobulin G antibodies (IgG) were added to dendritic cell cultures during both differentiation and maturation, and the resulting cellular messenger RNA (mRNA) and culture supernatants were tested by microarray and enzyme-linked immunoassay for molecules related to inflammatory pathways. Results: We identified unique mRNA and secreted protein signatures that were induced by different glycoforms of IgG during dendritic cell differentiation and maturation. Among the variety of mRNA and proteins induced by the sialic acidrich IgG fraction, we found a dramatic increase in levels of the melanoma growth factor CXCL1. Conclusions: Our findings support the concept that alternate glycoforms of IgG induce differing functional programs of dendritic cell differentiation and maturation. The data also support the concept that the functional phenotype of IgG is related to glycosylation. Thus, subtle changes in glycan structure can change the effector function of IgG from an inflammatory to an anti-inflammatory program. This work highlights the importance of the interface between tumors and the immune system, revealing a potential explanation as to why tumors persist and progress despite potent immune responses against them.

Keywords

• tumor immunity
• anti-inflammatory
• NY-ESO-1
• immunoglobulin G
• glycosylation
• sialic acid
• dendritic cells
• melanoma