Endogenous antibody responsiveness to epidermal growth factor receptor is associated with immunoglobulin allotypes and overall survival of patients with glioblastoma

The tumor-associated antigen epidermal growth factor receptor (EGFR) is overexpressed in 40%–60% of patients with malignant gliomas, the most common type of primary brain tumor, which is mostly incurable. EGFR amplification is frequently accompanied by an intragenic rearrangement that produces EGFR variant (v)III, which is tumor specific. Amplification and overexpression of both EGFR and EGFRvIII has been shown to be associated with worse prognosis in glioma patients.1 These observations have made EGFR an attractive target for both active (vaccine) and passive (antibody) immunotherapies against gliomas.2,3 Identification and understanding of the putative host genetic factors that might influence the magnitude of naturally occurring immune responses to EGFR and EGFRvIII is an important prerequisite to successfully designing vaccines and therapeutic antibodies against gliomas. This knowledge would also be important for a proper evaluation of vaccine efficacy trials. Thus, some people could be naturally high responders to EGFR and EGFRvIII, while others could be low responders. A lack of understanding of the host genetic factors involved in EGFR/EGFRvIII immunity hinders effective immunological intervention in glioblastoma and confounds the evaluation of ongoing vaccine efficacy trials. Immunoglobulin γ marker (GM) and κ marker (KM) allotypes, hereditary antigenic determinants of γ and κ chains, respectively,4,5 have been shown to be associated with immune responsiveness to a variety of antigens—infectious agents, vaccines, autoantigens, including some tumor-associated antigens5–11—but their possible contribution to immunity to EGFR and EGFRvIII has not been evaluated. The importance of Ig genes and humoral immunity in the pathogenesis of solid tumors has been underscored by a recent comprehensive analysis of human gene expression.12 This analysis identified the Ig κ constant (IGKC) gene as a strong prognostic marker in human solid tumors, providing a compelling rationale for investigating the role of KM alleles, genetic variants of IGKC, in the immunopathogenesis of these tumors. It is known that Fcγ receptor (FcγR)–mediated uptake of antigen-antibody complexes can enhance antigen presentation, which provides a good rationale for investigating the role of FcγR genotypes in humoral immunity to EGFR and EGFRvIII. Thus, different FcγR genotypes (of antigen presenting cells) could differentially influence the uptake of IgG opsonized EGFR antigens for presentation to helper T cells, resulting in antigen-specific B-cell activation. FcγR genotypes have been shown to be associated with the magnitude of humoral immunity to some tumor-associated antigens.13 The aim of the present investigation was to determine whether the magnitude of antibody responsiveness to EGFR and EGFRvIII was associated with particular GM, KM, and FcγR genotypes and whether antibody levels were associated with the overall survival of patients with glioblastoma multiforme (GBM). We found that antibody responsiveness to both EGFR and EGFRvIII was associated with particular GM alleles, and higher antibody levels correlated with longer survival.