Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma

Clin Cancer Res. 2016 Jul 1;22(13):3383-97. doi: 10.1158/1078-0432.CCR-15-2224. Epub 2016 Mar 9.

Abstract

Purpose: Reduced uninvolved immunoglobulin (Ig) levels are a hallmark of multiple myeloma. We previously showed that B-cell maturation antigen (BCMA) is solubilized and at high levels in multiple myeloma patient serum. We hypothesize that soluble BCMA binds B-cell-activating factor (BAFF) preventing its function to stimulate late B cells, and would result in lower polyclonal antibody levels in these patients.

Experimental design: Mice were dosed with recombinant human BCMA (rhBCMA) and BCMA-BAFF complexes were analyzed in plasma, and its effects on antibody and Ig heavy chain mRNA levels determined. Using flow cytometry, BAFF binding to B cells was examined in the presence of rhBCMA and sera from multiple myeloma patients. In multiple myeloma sera, BCMA-BAFF complex formation and BCMA, IgA, IgG levels, and heavy-light chain isoform pair levels were determined.

Results: rhBCMA-BAFF complexes formed in immune-competent and deficient mice. Mice with human multiple myeloma xenografts, which contain plasma hBCMA and hBCMA-BAFF complexes, showed reduced plasma-free BAFF levels. rhBCMA administered to immune competent mice markedly reduced plasma IgA, IgG, and IgM levels and splenic Ig heavy chain mRNA levels. In serum from multiple myeloma patients, BCMA-BAFF complexes were detected and BAFF levels were reduced. Multiple myeloma patient sera containing BCMA prevented binding of BAFF to B cells. There is an inverse correlation between serum BCMA and uninvolved polyclonal Ig level in multiple myeloma patients.

Conclusions: Our results show that soluble BCMA sequesters circulating BAFF, thereby preventing it from performing its signaling to stimulate normal B-cell and plasma cell development, resulting in reduced polyclonal antibody levels in multiple myeloma patients. Clin Cancer Res; 22(13); 3383-97. ©2016 AACR.

MeSH terms

  • Animals
  • B-Cell Activating Factor / metabolism*
  • B-Cell Maturation Antigen / metabolism*
  • B-Lymphocytes / immunology
  • Cell Line, Tumor
  • Humans
  • Immunoglobulin A / blood*
  • Immunoglobulin G / blood*
  • Immunoglobulin Heavy Chains / blood
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Light Chains / blood
  • Immunoglobulin Light Chains / genetics
  • Immunologic Deficiency Syndromes / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, SCID
  • Multiple Myeloma / pathology*
  • Multiprotein Complexes / blood
  • Multiprotein Complexes / genetics
  • Protein Isoforms / blood
  • Protein Isoforms / genetics
  • Xenograft Model Antitumor Assays

Substances

  • B-Cell Activating Factor
  • B-Cell Maturation Antigen
  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin Heavy Chains
  • Immunoglobulin Light Chains
  • Multiprotein Complexes
  • Protein Isoforms
  • TNFRSF17 protein, human
  • TNFSF13B protein, human