IgG and FcγR genotypes and humoral immunity to mucin 1 in prostate cancer
Introduction
Mucin 1 (MUC1) is a membrane-bound glycoprotein that is expressed at low levels in healthy tissues but overexpressed in the majority of adenocarcinomas, including prostate cancer [1], [2]. Because its expression correlates with advanced cancer stage, high Gleason grade, angiogenesis, and prostate cancer death, MUC1 is an ideal target for therapeutic intervention [3], [4], [5]. Anti-MUC1 antibody dependent mechanisms appear to contribute to tumor cell lysis in prostate cancer [6], but the host genetic factors that might regulate these mechanisms have not been identified. Identification and understanding of the host genetic factors that influence endogenous immune responses to MUC1 is an important prerequisite to successfully designing MUC1-based active (vaccine) and passive (antibody) immunotherapy against this malignancy.
Immunoglobulin GM allotypes, polymorphic variants in the constant region of γ chains[7], and Fcγ receptor (FcγR) genes have been shown to be associated with antibody responsiveness to some tumor-associated antigens [8], [9], [10], [11], [12], but their putative role in humoral immunity to MUC1 in prostate cancer has not been examined. A recent comprehensive analysis of human gene expression has identified immunoglobulin κ constant (IGKC) gene as a strong prognostic marker in human solid tumors [13], a finding that provides a strong rationale for investigating the role of KM alleles, genetic variants of IGKC [7], in the immunobiology of prostate cancer. There is increasing evidence that epistasis—modification of the action of a gene by one or more other genes—plays a significant role in human diseases. Almost all GM alleles are expressed in the Fc region of γ chains, making them the most likely candidates in the genome for epistatic interactions with FcγR alleles. Therefore, the aim of the present investigation was to determine whether FcγRIIa, FcγRIIIa, GM, and KM alleles—individually or in particular epistatic combinations—contribute to the inter-individual variability in the magnitude of antibody responsiveness to MUC1 in patients with prostate cancer.
Section snippets
Study subjects
The experimental design used was case-only design, which included prostate cancer patients presenting at the Hollings Cancer Center, Medical University of South Carolina. Buffy coat and plasma samples were obtained from 127 Caucasian American (CA) and 76 African American (AA) patients with histologically verified adenocarcinoma of the prostate. The study protocol was approved by the institutional IRB. The samples were kept frozen in the cancer center’s tissue bank until required. Age, Gleason
Results
Table 1 presents the anti-MUC1 antibody levels in relation to various patient characteristics. Anti-MUC1 antibody levels were not significantly associated with age, cancer stage or Gleason score in CA patients with prostate cancer. In AA patients, however, anti-MUC1 antibody levels trended toward a positive correlation with Gleason score (p = 0.065).
The distribution of GM, KM, and FcγR genotypes among CA study subjects in relation to the mean levels of IgG antibodies (ELISA units/μl) to MUC1 is
Discussion
The results presented here show an association between homozygosity for the V allele of FcγRIIIa and low antibody responsiveness to MUC1 in CA patients with prostate cancer. The V allele is associated with higher levels of antibody-dependent cellular cytotoxicity (ADCC) mediated by anti-MUC1 antibodies [20], but its role in the generation of endogenous anti-MUC1 antibody responses is not known. One mechanism underlying the observed association could involve FcγRIIIa-mediated antigen
Acknowledgments
This work was supported in part by a grant from the US Department of Defense (W81XWH-10-1-0479) and by the Biorepository & Research Pathology Services Shared Resource, Hollings Cancer Center, Medical University of South Carolina. We are grateful to the patients and their physicians for their participation and blood donation. We thank Shizhong Bu for assistance in genotyping assays.
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Immunologic disparities in prostate cancer between American men of African and European descent
2021, Critical Reviews in Oncology/HematologyCitation Excerpt :Interestingly, the authors observed that the overall baseline expression levels of MICA were lower in AA–derived cells (MDA-PCa-2b) relative to EA–derived cells (LNCaP and DU-145), and they established these cell lines as an in vitro model to study race-specific aspects of MICA biology in prostate cancer. Pandey et al. were the first to observe the immune-biologic role of FcγRIIIa and KM loci in humoral immunity to mucin-1 (MUC1) in prostate cancer (Pandey et al., 2013). The authors suggested that this pathway is uniquely enriched in AA due to the varying frequency of the KM1 gene.
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Suggestive evidence that Fc variants of IgG2 and FcγRIIa loci interact to contribute to the risk of prostate cancer
2013, Human ImmunologyCitation Excerpt :Immunoglobulin GM allotypes, genetic markers of γ chains, have been reported to be associated with the risk and protection of many diseases, including some malignant diseases [1–7], but their putative role in the etiopathogenesis of prostate cancer has hitherto not been examined. Recent evidence [8] suggests that particular alleles of FcγR and KM loci contribute to the magnitude of humoral immunity to the tumor-associated antigen mucin 1, whose expression correlates with advanced cancer stage, high Gleason grade, angiogenesis, and prostate cancer death [9,10]. This provides an excellent rationale for determining whether these genes are risk factors for the development of prostate cancer.