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.

转移性骨病（MBD）是晚期实体恶性肿瘤患者常见且致命的并发症。 程序性细胞死亡蛋白 1 (PD-1) 等免疫检查点抑制剂 (ICIs) 彻底改变了癌症 过去十年来，ICIs 对 MBD 的积极影响因某些免疫因素而减弱。 相关骨骼不良事件（irSAE），包括新骨病变的形成、骨吸收增加、 和椎体压缩性骨折。骨、免疫和骨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）质量，影响骨 机械完整性，并影响治疗反应，但 OIO 目前在 MBD 受体中尚未得到充分研究。 核因子 kappa-β (RANK) 激活剂及其配体 (RANKL) 可能被认为是 OIO 但它们在 ICI 中的作用仍未被探索。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 我们研究了 RANK/RANKL 和 PD-1 信号传导的调节。 OIO 可能支持 T 细胞激活，同时抑制破骨细胞活性，从而降低病情恶化的风险 骨 ECM 质量和机械完整性并产生协同抗癌功效，因此，我们将 (1) 表征转移性人骨中 OIO 相关 ECM 生物标志物的表达并制定预后 骨脆性特征；(2) 评估联合 RANKL 和 PD-1 阻断对骨 ECM 的影响 PCa 骨转移 (BM) 小鼠模型的质量、机械完整性和抗癌功效。 来自腰椎的人小梁骨核心，含有溶骨性、骨硬化性和混合性 转移性病灶将被压缩至无法测量骨机械性能。 病变破坏载荷的分布，将选择适当的阈值来创建二元测量 骨脆性的相关骨 ECM 生物标志物及其翻译后修饰将被提取。 使用混合效应多项逻辑回归对每个病变的最小生物标志物集进行建模。 我们将在不同的模型中进一步验证这些基于 OIO 的生物标志物。 溶骨性和骨硬化性 PCa BM 并评估抗 RANKL 在减轻骨脆性方面的功效 抗 PD1 疗法的设置本研究的结果将扩展目前对 PD1 效应的理解。 转移及其治疗对骨基质质量和机械完整性的 OIO 相关 ECM 标志物的影响。 调节病变异质性并预测脆性将提供功能相关性的新分子信息 此外，还可以推动免疫介导的骨重塑机制和 通过联合阻断 RANKL 和 PD-1 减轻骨脆性有助于风险适应选择 正在进行的和后续的治疗。