LAUSR

A proliferation inducing ligand (APRIL), abundant in serum samples of multiple myeloma (MM) patients, promotes MM cell progression in vivo predominantly via MM-specific receptor B cell maturation antigen (BCMA) (Blood. 2016; 127:3225). Here, we study whether APRIL directly regulate non-MM subpopulations to influence immunosuppressive bone marrow (BM) milieu and further define molecular mechanisms regulating these processes. First, transmembrane activator and calcium modulator (TACI) protein, the other APRIL receptor expressed at lower levels than BCMA on MM cell membrane, is consistently expressed at higher levels on CD4+CD25 high FoxP3 high T regulatory (Treg) vs autologous CD4+CD25- conventional T cells (Tcon) from MM patients (n=10, p 10-fold in purified Tregs vs autologous Tcon (n=12, p high Treg vs paired TACI low/- Tcon. Finally, APRIL upregulates CD19+CD24 high CD38 high B regulatory cells (Breg) which interact with MM cells in the BM to confer an immunosuppressive microenvironment. Importantly, APRIL-induced Breg has higher IL-10, which is blocked by a blocking APRIL monoclonal antibody. Taken together, we are the first to characterize significantly high TACI expression that is functional in immune checkpoint Treg and Breg subsets which barely express BCMA. Importantly, we identify additional biological functions of APRIL in regulating immunosuppression via specific TACI- but not BCMA-mediated signaling cascades in the MM BM milieu, further supporting targeting this mechanism-based immunotherapeutic pathway to simultaneously target MM cells and revert immunosuppression. Citation Format: Yu-Tzu Tai, Liang Lin, Liji Xing, Liji Xing, Kenneth Wen, Nikhil Munshi, Paul Richardson, Kenneth Anderson. A proliferation-inducing ligand (APRIL) directly impacts immune regulatory subsets to regulate suppressive multiple myeloma bone marrow microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3832.