APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment

• Published in: Blood 2016-06, Vol.127 (25), p.3225-3236
• Main Authors: Tai, Yu-Tzu, Acharya, Chirag, An, Gang, Moschetta, Michele, Zhong, Mike Y., Feng, Xiaoyan, Cea, Michele, Cagnetta, Antonia, Wen, Kenneth, van Eenennaam, Hans, van Elsas, Andrea, Qiu, Lugui, Richardson, Paul, Munshi, Nikhil, Anderson, Kenneth C.
• Format: Article
• Language: English
• Subjects: Animals; B-Cell Maturation Antigen - genetics; B-Cell Maturation Antigen - physiology; Bone Marrow - pathology; Bone Marrow - physiology; Cell Line, Tumor; Cell Proliferation - genetics; Cellular Microenvironment - genetics; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Immune Tolerance - genetics; Lymphoid Neoplasia; Mice; Mice, SCID; Multiple Myeloma - genetics; Multiple Myeloma - pathology; Osteoclasts - pathology; Osteoclasts - physiology; Tumor Necrosis Factor Ligand Superfamily Member 13 - genetics; Tumor Necrosis Factor Ligand Superfamily Member 13 - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2016-01-691162

Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM. •APRIL/BCMA activation promotes MM proliferation, survival, and immunosuppression in vitro and in vivo.•Targeting the APRIL/BCMA pathway represents a promising mechanism-based immunotherapy to target MM and overcome drug resistance.