The role of extracellular matrix quality in the prediction of metastasis-induced skeletal fragility and response to immunotherapy

细胞外基质质量在预测转移引起的骨骼脆性和免疫治疗反应中的作用

• 批准号: 10742484
• 负责人: Stacyann R Bailey
• 金额: $ 39.26万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742484
• 关键词: Address; Adjuvant; Adverse event; Affect; Animals; Architecture; Attenuated; Binding; Biological Markers; Bone Diseases; Bone Marrow; Bone Matrix; Bone Resorption; Bone Tissue; Bone remodeling; CD8-Positive T-Lymphocytes; Cadaver; Cells; Collagen Type I; Competence; Complication; Compression Fracture; Custom; Development; Extracellular Matrix; Extracellular Matrix Proteins; FLT3 ligand; Failure; Flow Cytometry; Fracture; Gelatinase B; Gene Expression; Heterogeneity; Human; Image; Immune; Immune checkpoint inhibitor; Immunoassay; Immunologic Markers; Immunotherapy; Interferon Type II; Interleukin-1; Interleukin-10; Interleukin-6; Knowledge; Lesion; Ligands; Linear Regressions; Logistic Regressions; Malignant Neoplasms; Malignant neoplasm of prostate; Mass Spectrum Analysis; Matrix Metalloproteinases; Measurement; Measures; Mechanics; Mediating; Metastasis Induction; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Modification; Molecular; Mus; Myeloid-derived suppressor cells; NF-kappa B; Neoplasm Metastasis; Oncology; Osteoblasts; Osteocalcin; Osteoclasts; Osteolysis; Osteolytic; Pathogenesis; Pathological fracture; Patients; Peptides; Polymerase Chain Reaction; Population; Post-Translational Protein Processing; Primary Neoplasm; Production; Proteomics; Regulatory T-Lymphocyte; Reporting; Resistance; Risk; Risk Reduction; Role; Sampling; Signal Transduction; Solid; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Time; Training; Transforming Growth Factor beta; Validation; Vertebral Bone; anti-PD-1; anti-PD1 therapy; anti-cancer; bone; bone fragility; bone loss; bone preservation; bone sialoprotein; bone strength; cancer therapy; cathepsin K; checkpoint inhibition; clinical imaging; collagenase 3; crosslink; cytokine; efficacy evaluation; imaging modality; immune checkpoint; improved; in vivo; lumbar vertebra bone structure; male; mechanical properties; mineralization; mouse model; neoplastic cell; osteoclastogenesis; osteopontin; precision medicine; predictive marker; prevent; prognostic signature; programmed cell death ligand 1; programmed cell death protein 1; prostate cancer cell; prostate cancer model; receptor; response; skeletal; spine bone structure; substantia spongiosa; treatment response; tumor

Metastatic bone disease (MBD) is a frequent and fatal complication in patients with advanced solid malignancies. Immune checkpoint inhibitors (ICIs) such as programmed cell death protein-1 (PD-1) have revolutionized cancer therapy over the past decade; however, the positive impact of ICIs in MBD is attenuated due to some immune- related skeletal adverse events (irSAEs), including the formation of new bone lesions, increased bone resorption, and vertebral compression fractures. The dynamic and multidirectional interactions between bone, immune, and tumor cells (osteoimmuno-oncology, OIO) can alter bone extracellular matrix (ECM) quality, influence bone mechanical integrity, and affect response to therapy, but OIO is currently underexamined in MBD. Receptor activator of nuclear factor kappa-β (RANK) and its ligand (RANKL) may be considered as key orchestrators of OIO yet their role in the setting of ICIs remain unexplored. Metastatic prostate cancer (PCa) cells, bone-forming osteoblasts, and activated T-cells trigger osteolysis independently by producing RANKL which binds to RANK on bone-resorbing osteoclasts (OCs). We hypothesize that modulation of RANK/RANKL and PD-1 signaling in OIO may support T-cell activation while inhibiting osteoclastic activity, thereby decreasing risk for worsening bone ECM quality and mechanical integrity and produce synergistic anticancer efficacy. Thus, we will (1) Characterize the expression of OIO-related ECM biomarkers in metastatic human bone and develop a prognostic signature of bone fragility; and (2) Evaluate the effects of combined RANKL and PD-1 blockade on bone ECM quality, mechanical integrity, and anti-cancer efficacy in mouse models of PCa bone metastases (BM). Cadaveric human trabecular bone cores from the lumbar vertebrae containing osteolytic, osteosclerotic, and mixed metastatic lesions will be compressed to failure for measurements of bone mechanical properties. Based on the distribution of the failure loads of the lesions, an appropriate threshold will be selected to create a binary measure of bone fragility. OIO-related bone ECM biomarkers and their posttranslational modifications will be extracted from each lesion. Using mixed effects multinomial logistic regression models a minimum set of biomarkers that predict bone fragility will be obtained. We will further validate these OIO-based biomarkers in distinct models of osteolytic and osteosclerotic PCa BM and assess the efficacy of anti-RANKL in mitigating bone fragility in the setting of anti-PD1 therapy. The results of this study will extend the current understanding of the effects of metastases and its treatment on bone matrix quality and mechanical integrity. OIO-related ECM markers that regulate lesion heterogeneity and predict fragility will provide new molecular information of functional relevance that can drive translational efforts. Moreover, the mechanisms of immune-mediated bone remodeling and mitigation of bone fragility by combined blockade of RANKL and PD-1 can aid in risk-adapted selection for ongoing and subsequent therapies.

转移性骨疾病（MBD）是晚期实体恶性肿瘤患者常见且致命的并发症。 免疫检查点抑制剂（ICI）如程序性细胞死亡蛋白-1（PD-1）已经彻底改变了癌症 在过去的十年中，ICIs治疗MBD的积极影响由于一些免疫- 相关骨骼不良事件（irSAE），包括新骨病变形成、骨吸收增加， 和脊椎压缩性骨折骨、免疫和免疫系统之间的动态和多向相互作用， 肿瘤细胞（骨免疫肿瘤学，OIO）可以改变骨细胞外基质（ECM）的质量，影响骨 机械完整性，并影响对治疗的反应，但OIO目前在MBD中的研究不足。受体 核因子κ-β激活因子（RANK）及其配体（RANKL）可能被认为是 然而，它们在国际刑事法院中的作用仍然没有得到探讨。转移性前列腺癌（PCa）细胞，骨形成 成骨细胞和活化的T细胞通过产生与RANK结合的RANKL独立触发骨质溶解 骨吸收破骨细胞（OC）。我们假设RANK/RANKL和PD-1信号转导的调节在 OIO可能支持T细胞活化，同时抑制骨细胞活性，从而降低恶化的风险。 骨ECM质量和机械完整性，并产生协同抗癌功效。我们将（1） 表征OIO相关ECM生物标志物在转移性人骨中的表达， （2）评估RANKL和PD-1联合阻断对骨ECM的影响 质量、机械完整性和在PCa骨转移（BM）小鼠模型中的抗癌功效。尸体 来自腰椎的人骨小梁核心含有溶骨性、骨钙素和混合骨钙素， 将转移病灶压缩至失效，以测量骨机械性能。基于 损伤失效载荷的分布，将选择适当的阈值以创建二元测量 骨骼脆弱性。将提取OIO相关的骨ECM生物标志物及其翻译后修饰 从每一个伤口。使用混合效应多项逻辑回归模型， 预测骨脆性。我们将进一步验证这些基于OIO的生物标志物在不同的模型， 溶骨性和骨质疏松性PCa BM，并评估抗RANKL在减轻 抗PD 1治疗的设置。这项研究的结果将扩展目前对 骨转移及其治疗对骨基质质量和机械完整性的影响。OIO相关ECM标志物， 调节病变异质性和预测脆性将提供新的功能相关的分子信息 可以推动翻译工作。此外，免疫介导的骨重建机制和 通过联合阻断RANKL和PD-1缓解骨脆性可有助于风险适应性选择， 持续和后续治疗。