Binding of MMP13 to Immune Checkpoint Receptor PD-1H links Bone Disease with Immune Suppression in Multiple Myeloma

MMP13 与免疫检查点受体 PD-1H 的结合将骨病与多发性骨髓瘤中的免疫抑制联系起来

• 批准号: 10472671
• 负责人: Jing Fu
• 金额: $ 46.91万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472671
• 关键词: Address; Adoptive Transfer; Antigen-Presenting Cells; Binding; Bone Diseases; Bone Resorption; Cell Lineage; Cells; Cytoskeletal Modeling; Cytoskeleton; Development; Disease; Disease Progression; Disease remission; Dose; Environment; Goals; Grant; Hand; Hematopoietic; Homologous Gene; Human; Immune; Immune Cell Suppression; Immune response; Immunologic Surveillance; Immunosuppression; In Vitro; Integral Membrane Protein; Knock-out; Lesion; Link; Lytic; Malignant Neoplasms; Matrix Metalloproteinases; Mediating; Metalloproteases; Mixed Lymphocyte Culture Test; Modeling; Multiple Myeloma; Mus; Osteoclasts; Pathologic; Pathway interactions; Patients; Phenotype; Play; Population; Proteins; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Signal Transduction; T-Lymphocyte; Testing; Time; Tumor-infiltrating immune cells; Work; antigen-specific T cells; bone; checkpoint receptors; collagenase 3; healing; immune checkpoint; in vivo; in vivo Model; knock-down; mouse model; novel; osteoclast activating factor; profiles in patients; programmed cell death protein 1; receptor; skeletal; treatment strategy

Multiple Myeloma (MM) bone disease remains one of the most dreaded complications of this still incurable cancer. Osteoclast-activating factors produced by MM cells induce osteoclasts, cause excessive bone resorption, and lytic bone lesions in ~80% of patients with poor healing even after achieving disease remission. In an effort to screen for potential myeloma-derived factors that activate osteoclasts, we identified matrix metalloproteinase 13 (MMP-13) to be highly secreted by primary MM cells and elevated in patients with bone disease. MMP-13 dose-dependently induces extensive bone resorption in vitro and in vivo. In MM bone disease mouse models, MMP-13 knockdown in MM cells significantly inhibits the development of lytic bone lesions, confirming that MMP-13 is critical for the development of multiple myeloma bone disease. It is of particular importance that MMP-13-dependent osteoclast activation occurs independently of its enzymatic activity, thereby establishing a new paradigm in the regulation of bone resorption. In overview, we have shown that MMP-13 plays a pivotal role in MM-induced bone destruction. We now have compelling evidence that immune checkpoint protein programmed death-1 homolog (PD-1H), a transmembrane protein broadly expressed on various hematopoietic cell lineages, serves as a previously unrecognized signaling receptor for MMP-13. We found that Pd-1h knockout in osteoclast blocks MMP-13-induced osteoclast activation and bone resorption, suggesting that MMP-13 binding to PD-1H plays a critical role in MM induced bone disease. Furthermore, we show that MMP-13 has a PD-1H mediated inhibitory effect on T cell expansion. Mmp-13-/- antigen presenting cells have increased stimulatory capacity on alloreactive T cells in vitro. In an in vivo model of alloreactivity, donor T cells expand significantly more in Mmp- 13-/- recipients, confirming that host MMP-13 expression mitigates the expansion of T cells. It is the central hypothesis of this grant that PD-1H is the key receptor for MMP-13 signaling and mediates its effects on osteoclasts, antigen presenting cells and T cells, resulting in bone resorption and immunosuppression in MM. We propose the following 4 Aims: 1) Define the role of PD-1H as the MMP-13 receptor in osteoclasts; 2) Characterize the role of the MMP-13/PD-1H axis in skeletal remodeling and MM bone disease; 3) Investigate the role of the MMP-13/PD-1H axis as an immune checkpoint in MM; and 4) Confirm the role of MMP-13/PD-1H axis in MM bone disease and immunosuppression in MM patients. Together, our findings highlight a previously unrecognized and new pathway of osteoclasts activation involving MMP-13/PD-1H axis that links the bone disease with immunosuppression in MM. We propose that our work will form the basis for novel treatment strategies in MM bone disease associated with suppressed immune response. Furthermore, this research will help to better understand the interaction between MM bone disease and the myeloma immune environment.

多发性骨髓瘤（mm）骨骼疾病仍然是最可怕的并发症之一 癌症。由MM细胞产生的破骨细胞激活因子诱导破骨细胞，导致骨过多 约80％的患者即使在疾病缓解后，愈合较差的患者的吸收和裂解骨病变。 为了筛选激活破骨细胞的潜在骨髓瘤来源的因素，我们确定了矩阵 金属蛋白酶13（MMP-13）由原代MM细胞高度分泌，并升高 疾病。 MMP-13剂量依赖性地诱导体外和体内广泛的骨吸收。在MM骨病中 小鼠模型，MM细胞中的MMP-13敲低显着抑制裂解骨病变的发展， 确认MMP-13对于多发性骨髓瘤骨骼疾病的发展至关重要。这是特别的 MMP-13依赖性破骨细胞激活的重要性是独立于其酶活性的，因此 在调节骨吸收时建立新的范式。在概述中，我们显示了MMP-13 在MM引起的骨骼破坏中起关键作用。 现在，我们有令人信服的证据表明免疫检查点蛋白编程的死亡1同源物（PD-1H），一个 跨膜蛋白在各种造血细胞谱系上广泛表达 MMP-13的先前未识别的信号受体。我们发现破骨细胞块中的PD-1H敲除 MMP-13诱导的破骨细胞激活和骨吸收，这表明MMP-13与PD-1H的结合起着A 在MM诱导骨病中的关键作用。此外，我们表明MMP-13具有PD-1H介导的抑制 对T细胞扩展的影响。 MMP-13 - / - 抗原呈递细胞具有增加的刺激能力 体外同种反应性T细胞。在同质性的体内模型中，供体T细胞在MMP-中的扩展明显更大 13 - / - 接受者，确认宿主MMP-13表达可缓解T细胞的膨胀。 这项赠款的中心假设是，PD-1H是MMP-13信号传导的关键受体 它对破骨细胞，抗原呈现细胞和T细胞的影响，导致骨吸收和 MM中的免疫抑制。我们提出以下4个目标：1）将PD-1H的作用定义为MMP-13 破骨细胞中的受体； 2）表征MMP-13/PD-1H轴在骨骼重塑和MM骨中的作用 疾病; 3）研究MMP-13/PD-1H轴作为MM中的免疫检查点的作用； 4）确认 MMP-13/PD-1H轴在MM骨骼疾病中的作用和MM患者的免疫抑制。在一起，我们的发现 突出显示了涉及MMP-13/PD-1H轴激活的先前未识别的新途径 这将骨骼疾病与MM中的免疫抑制联系起来。我们建议我们的工作将构成新颖的基础 与抑制免疫反应有关的MM骨疾病的治疗策略。此外，这个 研究将有助于更好地了解MM骨病与骨髓瘤免疫之间的相互作用 环境。