Biomaterial approaches to attenuate macrophage recognition of "self"-signals from cancer cells

生物材料方法减弱巨噬细胞对癌细胞“自身”信号的识别

• 批准号: 9914098
• 负责人: Lawrence J Dooling
• 金额: $ 6.74万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914098
• 关键词: Adoptive Cell Transfers; Anti-CD47; Antibodies; Apoptosis; Area; Artificial nanoparticles; Attenuated; Biochemical; Biocompatible Materials; Biology; Blood; Bone Marrow; CD47 gene; CD47-SIRPα; Cancer Biology; Cell Adhesion; Cell Surface Receptors; Cell Therapy; Cells; Cellular biology; Clinical Trials; Cues; Data; Discipline; Drug Delivery Systems; Eating; Elasticity; Engineering; Extracellular Matrix; Fellowship; Goals; Hydrogels; Immune; Immunology; Injections; Innate Immune System; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediator of activation protein; MicroRNAs; Modeling; Monoclonal Antibody Therapy; Mus; Pathway interactions; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Phenotype; Physiological; Polymers; Positioning Attribute; Process; Proteins; Research; Research Personnel; Research Training; Safety; Signal Pathway; Signal Transduction; Solid Neoplasm; Surface; Therapeutic Agents; Tissues; Traction; Translations; Tumor-associated macrophages; Xenograft Model; base; bone engineering; cancer cell; cancer therapy; cell motility; cellular targeting; controlled release; experience; improved; insight; macrophage; monocyte; mouse model; nanoparticle; nanoparticle drug; overexpression; polyacrylamide hydrogels; receptor; response; skills; small molecule; success; targeted treatment; trafficking; translational impact; tumor; tumor microenvironment

Project Summary/Abstract In this project, two biomaterial approaches will be developed to investigate how macrophages are reprogrammed by their microenvironment and to block the undesired consequences of this reprogramming. Macrophages are capable of infiltrating solid tumors and can phagocytose cancer cells provided that inhibitory “self”-signaling pathways are blocked and pro-phagocytic signals are present. This approach is the basis for a recent adoptive cell transfer therapy using engineered bone marrow-derived macrophages (eMDMs) to treat solid tumors. While this therapy was shown to be safe and effective at shrinking tumors in mouse models, further improvements are required for successful translation. A major barrier that must be overcome is the relatively rapid loss of the phagocytic ability of eMDMs and their acquisition of an M2-like phenotype that is similar to tumor-associated macrophages. Macrophage reprogramming by the tumor microenvironment results in increased expression of SIRPα, a cell surface receptor that recognizes the CD47 “marker of self” protein that is overexpressed on many cancer cells. It is hypothesized here that increased SIRPα on reprogrammed macrophages sensitizes them to CD47 on cancer cells and inhibits phagocytosis. In Aim 1, polymeric nanoparticles will be used to deliver small molecule drugs and microRNAs to eMDMs in order to maintain a low SIRPα, phagocytic phenotype. Drug-loaded nanoparticles will be taken up by eMDMs prior to their injection into tumor-bearing mice. Localized, sustained release of drugs that suppress SIRPα expression is anticipated to prolong phagocytosis and to improve tumor shrinkage. In Aim 2, engineered polyacrylamide hydrogels will be used to investigate how substrate stiffness acts a physical cue to regulate self- signaling between macrophages and cancer cells through the CD47-SIRPα axis. Preliminary data suggest that SIRPα expression increases on stiff substrates, providing a potential mechanism by which stiff tumor microenvironments might reprogram macrophages and inhibit phagocytosis of cancer cells. Together, the approaches in Aims 1 and 2 demonstrate how biomaterials can be used to study and engineer biology, specifically immune cells. Successful completion of these aims will have a significant translational impact (i.e. the improvement of macrophage based therapies) and provide important new insights into cell biology and mechanobiology (i.e. an understanding of how physical cues influence self-signaling in the innate immune system). These aims are part of the Research Training Plan for my postdoctoral fellowship and provide the opportunity for me to acquire both depth by enhancing my biomaterials skill set and breadth by developing new expertise in cell biology, cancer biology, and immunology. This will position me for success in attaining my goal of becoming an independent investigator working at the interface of these disciplines.

项目摘要/摘要 在这个项目中，将开发两种生物材料方法来研究巨噬细胞的方式 通过其微环境重新编程，并阻止此重编程的不需要后果。 巨噬细胞能够浸润实体瘤，可以吞噬癌细胞，规定抑制性 “自我” - 信号途径被阻止，并且存在促孢细胞信号。这种方法是 最近使用工程骨髓衍生的巨噬细胞（EMDMS）来治疗的细胞转移疗法 实体瘤。虽然这种疗法被证明可以安全有效地缩小小鼠模型中的肿瘤，但进一步 成功翻译需要改进。必须克服的主要障碍是相对 EMDMS的吞噬能力的快速丧失及其获得类似于M2的表型 肿瘤相关的巨噬细胞。巨噬细胞通过肿瘤微环境重编程导致 SIRPα的表达增加，SIRPα是一种识别CD47“自我标记”蛋白的细胞表面受体 在许多癌细胞上过表达。在这里假设在重新编程中增加了SIRPα 巨噬细胞在癌细胞上将其感知到CD47并抑制吞噬作用。 在AIM 1中，聚合物纳米颗粒将用于将小分子药物和microRNA传递给EMDM 为了维持较低的SIRPα，吞噬表型。负载的纳米颗粒将由EMDMs占用 在注射肿瘤小鼠之前。抑制SIRPα的局部，持续释放的药物 预计表达会延长吞噬作用并改善肿瘤收缩。在AIM 2中，工程 聚丙烯酰胺水凝胶将用于研究底物刚度如何作用物理提示以调节自我 通过CD47-SIRPα轴之间的巨噬细胞和癌细胞之间的信号传导。初步数据表明 SIRPα表达在刚性底物上增加，提供了僵硬肿瘤的潜在机制 微环境可能会重新编程巨噬细胞并抑制癌细胞的吞噬作用。 AIM 1和2中的方法共同证明了如何使用生物材料来研究和工程 生物学，特别是免疫细胞。这些目标的成功完成将产生重大的翻译影响 （即改善基于巨噬细胞的疗法），并为细胞生物学和 机械生物学（即对物理线索如何影响先天免疫中的自给自足的理解 系统）。这些目标是我博士后研究金的研究培训计划的一部分，并提供 我有机会通过开发新的新生物材料技能和广度来获得两种深度 细胞生物学，癌症生物学和免疫学方面的专业知识。这将使我成功实现我的目标 成为在这些学科界面工作的独立研究者。