Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication
Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication
复制标题
破骨细胞促进多发性骨髓瘤中的免疫抑制微环境：治疗意义。
DOI：
10.1182/blood-2016-03-707547
复制
发表时间：
2016-09-22
期刊：
影响因子：
20.3
通讯作者：
Anderson, Kenneth C.
中科院分区：
文献类型：
--
作者：
An, Gang;Acharya, Chirag;Anderson, Kenneth C.
骨髓瘤细胞强烈增强破骨细胞（OCs）的数量和活性，导致多发性骨髓瘤（MM）患者出现明显的骨病变。至于支持骨髓瘤的OCs是否也诱导抑制性免疫骨髓（BM）微环境，其机制尚不明确。在这里，我们首先证明了OCs通过直接抑制增殖的CD4（+）和CD8(+) T细胞，显著保护MM细胞免受T细胞介导的细胞毒性。免疫检查点分子程序性死亡配体1 （PD-L1）、半乳糖凝集素-9、疱疹病毒进入介质（HVEM）和CD200，以及t细胞代谢调节因子吲哚胺2,3 -双加氧酶（IDO）和CD38在破骨细胞发生过程中显著上调。重要的是，除了CD38外，OCs中的这些分子水平高于MM细胞。抗pd - l1单克隆抗体（mAb）和IDO抑制剂部分克服了oc抑制的T细胞对MM细胞的反应，证实了它们在oc抑制的MM细胞被细胞毒性T细胞裂解中的作用。此外，OCs分泌的半乳糖凝集素-9和增殖诱导配体（四月份）在破骨细胞发生过程中显著上调。半乳糖凝集素-9特异性诱导T细胞凋亡，同时保留单核细胞和MM细胞。APRIL诱导MM细胞中PD-L1的表达，通过OCs提供额外的免疫抑制。此外，CD38在破骨细胞形成过程中显著上调。当被抗cd38单抗靶向时，OCs的抑制t细胞功能减轻，与HVEM和IDO的下调有关。综上所述，这些结果确定了OCs中抑制MM - BM环境所必需的多种免疫蛋白和细胞因子的表达。这些结果进一步支持联合靶向这些分子来提高抗mm免疫。
The number and activity of osteoclasts (OCs) are strongly enhanced by myeloma cells, leading to significant bone lesions in patients with multiple myeloma (MM). Mechanisms remain elusive as to whether myeloma-supporting OCs also induce suppressive immune bone marrow (BM) microenvironment. Here, we first show that OCs significantly protect MM cells against T-cell-mediated cytotoxicity via direct inhibition of proliferating CD4(+) and CD8(+) T cells. The immune checkpoint molecules programmed death ligand 1 (PD-L1), Galectin-9, herpesvirus entry mediator (HVEM), and CD200, as well as T-cell metabolism regulators indoleamine 2, 3-dioxygenase (IDO), and CD38 are significantly upregulated during osteoclastogenesis. Importantly, the levels of these molecules, except CD38, are higher in OCs than in MM cells. Anti-PD-L1 monoclonal antibody (mAb) and IDO inhibitor partly overcome OC-inhibited T-cell responses against MM cells, confirming their roles in OC-suppressed MM cell lysis by cytotoxic T cells. In addition, Galectin-9 and a proliferation-induced ligand (APRIL), secreted by OCs, are significantly upregulated during osteoclastogenesis. Galectin-9 specifically induces apoptosis of T cells while sparing monocytes and MM cells. APRIL induces PD-L1 expression in MM cells, providing additional immune inhibition by OCs. Moreover, CD38 is significantly upregulated during osteoclastogenesis. When targeted by an anti-CD38 mAb, suppressive T-cell function by OCs is alleviated, associated with downregulation of HVEM and IDO. Taken together, these results define the expression of multiple immune proteins and cytokines in OCs essential for suppressive MM BM milieu. These results further support the combination of targeting these molecules to improve anti-MM immunity.