Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma?

Abstract

Multiple myeloma (MM) has emerged as the next most likely oncological or hematological disease indication amenable for cellular immunotherapy. Much of the attention has been focused on B cell maturation antigen (BCMA) as a unique cell surface protein on myeloma cells that is available for monoclonal antibodies, antibody drug conjugates (ADCs), T-cell redirecting bispecific molecules, and chimeric antigen receptor (CAR) T cell targeting. BCMA is a member of the tumor necrosis factor receptor (TNFR) superfamily that binds two ligands B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) and mediates the growth and survival of plasma and MM cells. Interestingly, transmembrane activator and CAML interactor (TACI), another TNFR superfamily member, also binds the same ligands and plays largely overlapping roles as BCMA in normal plasma and malignant MM cells. In this article, we review the biology of TACI, focusing on its role in normal B and plasma cells and malignant MM cells, and also discuss various ways to incorporate TACI as a potential target for immunotherapies against MM.

Association of Common Variants of TNFSF13 and TNFRSF13B Genes with CLL Risk and Clinical Picture, as Well as Expression of Their Products—APRIL and TACI Molecules

“…Recently, the TACI-APRIL interaction has been studied in multiple myeloma (MM) cells and it has been demonstrated for regulatory T cells (Tregs) that this interaction may contribute to the immunosuppressive microenvironment of MM. Tregs expressed significantly higher levels of TACI receptors [ 38 ]. Hence, it has been postulated that APRIL may promote survival and proliferation of Tregs [ 38 ].…”

“…Tregs expressed significantly higher levels of TACI receptors [ 38 ]. Hence, it has been postulated that APRIL may promote survival and proliferation of Tregs [ 38 ]. Furthermore, it has been also shown that TACI-mediated APRIL signalling had impact on an increased number of regulatory B cells (Bregs) from the bone marrow of MM patients as well as on higher production of IL-10 by Bregs [ 38 ].…”

“…Hence, it has been postulated that APRIL may promote survival and proliferation of Tregs [ 38 ]. Furthermore, it has been also shown that TACI-mediated APRIL signalling had impact on an increased number of regulatory B cells (Bregs) from the bone marrow of MM patients as well as on higher production of IL-10 by Bregs [ 38 ]. Collectively, these results imply that APRIL may play a role in establishing an immunosuppressive tumour microenvironment in bone marrow of MM patients [ 38 ].…”

“…Furthermore, it has been also shown that TACI-mediated APRIL signalling had impact on an increased number of regulatory B cells (Bregs) from the bone marrow of MM patients as well as on higher production of IL-10 by Bregs [ 38 ]. Collectively, these results imply that APRIL may play a role in establishing an immunosuppressive tumour microenvironment in bone marrow of MM patients [ 38 ]. Taking the above into consideration, it can be anticipated that TACI-APRIL interaction may also contribute to the immunosuppressive tumour microenvironment in CLL, and if this happens, CLL patients with genotypes associated with higher expression of APRIL and/or TACI may progress to more aggressive forms of CLL.…”

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

“…In addition, there is evidence that these two homologous members of the tumor necrosis factor (TNF) superfamily play roles in myeloma cell viability and proliferation [41]. Two other TNF family members -transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA), located on the surface of myeloma cells, serve as ligands for both BAFF and APRIL [42]. While the respective BAFF and APRIL inhibitors, atacicept and tabalumab (LY2127399), as well as the anti-APRIL mAb BION-1301, showed poor efficacy in MM trials [43][44][45], BCMA has surfaced as a compelling target in anti-myeloma drug research [46].…”