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: 10299234
• 负责人: Jing Fu
• 金额: $ 49.42万
• 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/10299234
• 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）骨病仍然是最可怕的并发症之一，仍然无法治愈