Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

摘要: The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple (MM). Mechanisms remain elusive as whether myeloma-supporting OCs also induce suppressive immune marrow (BM) microenvironment. Here, we first show that significantly protect MM cells against T-cell-mediated cytotoxicity via direct inhibition proliferating CD4(+) CD8(+) T cells. checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), CD200, well T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), CD38 upregulated during osteoclastogenesis. Importantly, the levels these molecules, except CD38, higher than Anti-PD-L1 monoclonal antibody (mAb) IDO inhibitor partly overcome OC-inhibited responses confirming their roles OC-suppressed cell lysis cytotoxic In addition, Galectin-9 a proliferation-induced (APRIL), secreted OCs, specifically induces apoptosis while sparing monocytes APRIL PD-L1 expression providing additional OCs. Moreover, is When targeted an anti-CD38 mAb, function alleviated, associated downregulation HVEM IDO. Taken together, results define proteins cytokines essential for BM milieu. These further support combination targeting improve anti-MM immunity.