Skip to main content
. 2021 Dec 6;13(23):6136. doi: 10.3390/cancers13236136

Figure 1.

Figure 1

Pathobiological function of validated MM target antigens commonly used in current MM immunotherapies. (A) CD38, a receptor and an ectoenzyme, regulates the conversion of NAD+ to ADO, which contributes to the immunocompromised tumor microenvironment. IL-6, an important MM growth, survival, and immunosuppressive cytokine, mainly produced by non-myeloma BM cells (i.e., BMSCs, MDSC, OC, and TAM), binds to IL-6R, which interacts with gp130 to activate the JAK1/2-STAT1/3 signaling pathway and subsequently downregulates CD38 expression in MM cells. (B) BCMA is the cognate receptor for APRIL and BAFF, which are present in the BM microenvironment. APRIL, an important plasma cell factor, preferentially binds to BCMA when compared with BAFF, to induce signaling pathways critical to promote survival, proliferation, and drug resistance, as well as immunosuppression of MM cells. BCMA expression is induced by BLIMP1, a key plasma cell transcriptional regulator, and BCMA protein is cleaved by gamma (γ)-secretase, resulting in the soluble form (sBCMA) that is detected in MM patient serum and correlated with disease advancement. (C) CD138, the transmembrane heparan sulfate proteoglycan syndecan-1, is overexpressed in malignant plasma cells and its levels are associated with increased proliferation and survival, as well as decreased apoptosis in MM cell lines and patient MM cells. Levels of shed CD138 (sCD138) cleaved by metalloproteinases and heparanase in MM patient serum samples are also linked to disease progression and sCD138 acts locally or distally with various effector molecules (i.e., IL-6, APRIL, and VEGF) to impact tumor progression. (D) SLAMF7, also named CS1, promotes adhesion of MM cells to BMSCs. The expression of SLAMF7 is regulated by the transcriptional factor IKZF1 (Ikaros), a MM-related target by lenalidomide and pomalidomide, in MM cells. Soluble SLAMF7 (sSLAMF7) is detected in patient serum and promotes MM cell growth via homophilic interaction with SLAMF7 on MM cells. Among these four MM antigens, BCMA has the most limited expression at the transcript and protein levels in plasma cells but no other normal tissues except a minute subset of plasmacytoid dendritic cell. ADO, adenosine; ADPR, ADP-ribose; APRIL, A proliferation inducing ligand; BAFF, B-cell activating factor; BMSC, bone marrow stromal cell; JAK, Janus kinase; MDSC, myeloid-derived suppressor cell; NAD+, nicotinamide adenine dinucleotide; OC, osteoclast; TAM, tumor-associated macrophages; VEGF, vascular endothelial growth factor.