Studies investigating the role of tumor-associated antigens (TAAs) in cancer diagnosis and progression have focused on the MUC1 antigen, which is overexpressed in most solid epithelial and non-solid hematological tumors including multiple myeloma (1‑3). Soluble MUC1 (sMUC1) levels were reported to be elevated in sera of patients with solid tumors such as breast carcinoma, and non-solid tumors such as multiple myeloma, using FDA approved sMUC1 assays CA15.3 and CA27.29 directed to the extracellular tandem repeat array (TRA) domain (3,4). However, despite the wide tumor distribution of MUC1, use of the CA15.3 and CA27.29 markers is confined to monitoring the prognosis and response to treatment in patients with advanced breast cancer (5) and it is not sensitive enough to be used for early diagnosis.
In contrast, naturally generated autoantibodies to TAAs are detectable even before the tumor is clinically apparent (6), and due to their lower fluctuation and longer half-life in the blood, they may be more appropriate for cancer diagnosis. Anti-MUC1 TRA autoantibody levels were shown to be higher in patients with breast cancer (7) and lower in multiple myeloma (3) patients compared to healthy individuals. One suggested cause for the variations in multiple myeloma patients relates to the presence of immune complexes between sMUC1 and the endogenously generated anti-MUC1 TRA antibodies (3). Bypassing this limitation can potentially be achieved by searching for anti-MUC1 autoantibodies generated to domains flanking the TRA.
Along with others, we have demonstrated the preferred immunogenicity of the signal peptide (SP) domain of MUC1 (8‑10). This short domain has promiscuous binding to multiple major histocompatibility complex (MHC) class I and II, a characteristic that supports its process and presentation on the cell surface of various tumor cells and antigen presenting cells (10). In the present study, we questioned whether MUC1’s SP domain preferred MHC class II binding, coupled with in silico prediction of B-cell epitopes, could lead to the induction of a natural anti-SP humoral response in multiple myeloma patients. Click here to download full research Article