Mechanisms and therapeutic targeting of osteoimmune functions of RANKL in breast cancer

RANKL在乳腺癌中的骨免疫功能的机制和治疗靶点

基本信息

批准号：
10586000
负责人：
Selvarangan Ponnazhagan
金额：
$ 44.67万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586000
关键词：
Address Adopted Affinity Antibodies Apoptosis Autocrine Communication Binding Bone Diseases Breast Cancer Cell Breast Cancer Model Breast Cancer Risk Factor Breast cancer metastasis CD8-Positive T-Lymphocytes Cell Therapy Cell physiology Cells Clinic Combination Drug Therapy Combined Modality Therapy Disease Disease Progression Double-Blind Method Engineering Environment G-Protein-Coupled Receptors Goals Homeostasis Human Human Pathology Immune Immune Targeting Immune system Immunocompetent Immunocompromised Host Immunosuppression Induction of Apoptosis Injections International Leucine-Rich Repeat Ligand Binding Ligands Link Macrophage Malignant Bone Neoplasm Mediator Metastatic Neoplasm to the Bone Metastatic breast cancer Molecular Monoclonal Antibodies Monoclonal Antibody Therapy Mus Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Nuclear Osteoclasts Osteolysis Outcome Study Pathology Pathway interactions Patients Phase Placebo Control Play Primary Neoplasm Production Protein Engineering Proteins Publishing Randomized Recurrent disease Refractory Resistance Role Signal Transduction Skeletal system Structure Systemic Therapy TNF-related apoptosis-inducing ligand TRANCE protein Testing Therapeutic Therapeutic Effect Tumor Promotion Tumor necrosis factor receptor 11b Variant antagonist bone chemotherapy cytokine design effector T cell exhaustion genetically modified cells high risk immune checkpoint blockade immune resistance improved in vivo in vivo Model malignant breast neoplasm monocyte mouse model neoplastic cell new combination therapies novel paracrine phase 3 study polarized cell programmed cell death ligand 1 programmed cell death protein 1 protein structure receptor receptor function skeletal skeletal-related events spatiotemporal targeted treatment taxane therapeutic target tumor tumor growth tumor microenvironment

项目摘要

Complexities in treating breast cancer (BCa) with bone metastasis are aggravated by a vicious protumorigenic pathology involving a shift in skeletal homeostasis towards aggressive osteoclast activity and polarization of myeloid cells, favoring M2 macrophage (MФ) and myeloid-derived suppressor cell (MDSC) accumulation as key mediators of immunosuppression. In addition to the tumor cells, protumorigenic myeloid cells contribute to the cascade by expressing checkpoint ligands, blunting antitumor functions of effector T cells. Hence, a better understanding of key signaling mechanisms that alter skeletal and immune homeostasis towards protumorigenic functions will enable the designing of new combination therapies targeting this biphasic effect. In this pursuit, we have identified that in addition to robust activation of osteoclast precursors, receptor activator of nuclear factor kappa-Β ligand (RANKL) plays an important role as an osteoimmune link in MФ polarization and programmed death-ligand 1 (PD-L1) expression. We identified that elevated RANKL from BCa cells induce paracrine effects on differentiation of monocytes to immunosuppressive M2 MФ in a spatiotemporal manner. Preliminary studies presented in this application indicate that whereas RANKL canonical autocrine signaling via RANK activates a feed-forward loop in BCa cells, non-canonical RANKL signaling enhances PD-L1 expression in M2 MФ and MDSCs via the leucine-rich repeat containing G-protein coupled receptor (Lgr4). Based on our published and preliminary findings, the overarching goal of this proposal is to expand our understanding on the pleiotropic mechanisms of RANKL in BCa immunosuppression and bone damage, and to test the potential of combining a novel osteoprotegerin (OPG) cell therapy without interfering in TNF-related apoptosis-inducing ligand (TRAIL) function, with checkpoint blockade and chemotherapies, to reverse tumor- associated pathology in the immune and skeletal systems. We recently adopted a protein structure-based engineering approach and identified a critical domain on OPG for TRAIL binding and successfully developed and validated in vivo an OPG variant (OPGY49R) that retains RANKL binding, but lacks TRAIL binding. Preliminary studies, directly comparing a cell-based, single-application OPGY49R treatment with multiple applications of a neutralizing RANKL mAb therapy indicated systemically stable levels of OPGY49R from a single injection and a significant decrease in CD8+ T cell exhaustion, compared to RANKL mAb treatment. More importantly, OPGY49R greatly decreased metastasis of primary tumors in vivo, demonstrating its potential advantage over the RANKL mAb, denosumab, which failed to delay bone metastasis or disease recurrence in patients with high-risk early- stage BCa in a recent international double-blinded randomized placebo-controlled, phase 3 study (D-CARE). This proposal will test this novel, biologically driven combination therapy approach by using immunocompetent mouse models of BCa, as applicable to both pre-metastatic and metastatic disease.

用骨转移治疗乳腺癌（BCA）的复杂性是由恶性杂种综合的病理学涉及将骨骼稳态转移向侵略性破骨细胞活性和极化的病理有利于M2巨噬细胞（MO）和髓样衍生的抑制细胞（MDSC）积累的髓样细胞作为钥匙免疫抑制的介体。除了肿瘤细胞外，杂型髓样细胞还有助于通过表达检查点配体的级联反应，效应T细胞的抗肿瘤功能。因此，更好了解将骨骼和免疫稳态改变为杂志的关键信号传导机制功能将使针对这种双相效应的新组合疗法的设计。在这种追求中，我们已经确定，除了破骨细胞前体的强化激活外，核因子的受体激活剂 kappa-β配体（RANKL）在MOS化和编程中作为骨免疫连接起重要作用死亡配体1（PD-L1）表达。我们发现BCA细胞的RANKL升高会诱导旁分泌作用关于单核细胞以时空的方式分化为免疫抑制M2的M2。初步研究在本应用程序中提出，表明RANKL经典的自分泌信号通过等级激活A BCA细胞中的前馈环，非典型的RANKL信号传导增强了M2 MO的PD-L1表达 MDSC通过富含亮氨酸的重复含有G蛋白偶联受体（LGR4）。根据我们已发表的初步发现，该提案的总体目标是扩大我们的了解BCA免疫抑制和骨骼损伤中RANKL的多效机制，以及测试结合新型骨蛋白蛋白蛋白（OPG）细胞疗法的潜力，而无需干扰TNF相关的凋亡诱导的配体（TRAIL）功能，具有检查点阻滞和化学疗法，以反向肿瘤免疫和骨骼系统中的相关病理。我们最近采用了基于蛋白质结构的工程方法并确定了OPG上的关键领域，以进行步道绑定并成功开发并在体内验证了一个保留RANKL结合但缺乏跟踪结合的OPG变体（OPGY49R）。初步的研究，直接比较了基于细胞的单应用OPGY49R处理与A的多种应用中和RANKL mAb疗法表明，单个注射和A 与RANKL MAB治疗相比，CD8+ T细胞耗尽的显着降低。更重要的是，OPGY49R 大大改善了体内原发性肿瘤的转移，证明了其在RANKL上的潜在优势 MAB，Denosumab，未能延迟高危早期患者的骨转移或疾病复发 BCA阶段在最近的国际双盲随机安慰剂对照，第三阶段研究（D-CARE）中。该建议将通过使用免疫能力来测试这种新颖的，生物学驱动的联合疗法方法 BCA的小鼠模型，适用于期前和转移性疾病。