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

Abstract

Purpose: Reduced uninvolved immunoglobulin (Ig) levels are a hallmark of multiple myeloma. We previously showed that Bcell 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. Ó2016 AACR.

Involvement of BAFF and APRIL in Resistance to Apoptosis of Acute Myeloid Leukemia

“…It is likely, therefore, that BCMA activation cause increased proliferation of AML cells what in turn may be associated with their increased sensitivity to chemotherapeutic drug, including commonly used AraC. On the other hand, soluble BCMA released from BCMA cells may reduce the anti-apoptotic APRIL and BAFF activity 12. This hypothesis, however, did not explain why only a small subset of AML cells show BCMA expression.…”

Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients

“…Its rapid turnover in the blood (24–36 hours half life) 45 compared to conventional Ig levels 36,37 would potentially allow for early determination of changes in clinical status. Preliminary results from monitoring our patients suggest that this is the case ( JR Berenson, 2017, unpublished observations ).…”

“…Specifically, the circulating protein has been implicated in the pathway that leads to immune deficiency in MM patients, a hallmark of the disease. 45 The shed TNF receptor acts as a decoy receptor and binds B-cell ligands including BAFF preventing them from performing their normal function to stimulate late B-cell development and their production of normal antibodies. Many groups are developing antibodies to BCMA as a therapeutic approach to combat myeloma and other plasma cell malignancies.…”

“…43 We have recently identified BCMA in serum and shown its levels are higher among patients with monoclonal gammopathies. 44 In mice, studies have shown that soluble BCMA has a half-life of approximately 24–36 hours 45 which is much faster than the turnover rates for IgG (21 days) and IgA (7 days), 36,37 suggesting that soluble BCMA levels can be used to evaluate the effect of a given treatment much more rapidly than through measurement of monoclonal antibody levels.…”

Cell‐ and Tissue‐Based Proteome Profiling and Dual Imaging of Apoptosis Markers with Probes Derived from Venetoclax and Idasanutlin

“…An important protein hit identified from tumor tissues is Tnfrsf17 (tumor necrosis factor receptor superfamily member 17A), which is associated with chronic lymphocytic leukemia (CLL) and common variable immunodeficiency. [15] Other protein hits identified from tissues include Apoa1, Gjd4, Ssbp1, Igfbp2, and ribosomal proteins,w hich are disease-related proteins (see Table S2). Overall, consistent with the labeling profiles,t he…”