HOMEOSTATIC CONTROL OF MACROPHAGE FCy RECEPTOR FUNCTION

巨噬细胞 FCy 受体功能的稳态控制

基本信息

批准号：
8730544
负责人：
Susheela Tridandapani
金额：
$ 32.37万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8730544
关键词：
Accounting Adjuvant Age Agonist Antibodies Antibody Therapy Binding Biological Cancer Patient Cell surface Cells Clinical Trials Effector Cell Engineering Enhancing Antibodies Evaluation Event Goals Guanine Nucleotide Dissociation Inhibitors Immunologic Receptors Immunosuppression Immunotherapy In Vitro Individual Inflammatory Knowledge Ligands Malignant Neoplasms Mediating Methods Modality Modeling Molecular Monoclonal Antibody Therapy Mus Natural Immunity Natural Killer Cells Patients Phagocytosis Phenotype Phosphoric Monoester Hydrolases Play Proteomics Quality of life Regulation Relative (related person)Roche brand of trastuzumab Role Sampling Solid Neoplasm TLR2 gene Testing Therapeutic Therapeutic antibodies Toll-like receptors Up-Regulation Work base cancer cell cancer immunotherapy cancer therapy cancer type clinically relevant human INPPL1 protein improved in vivo innate immune function innovation macrophage monocyte neoplastic cell neutrophil novel prevent receptor response therapeutic target tumor

项目摘要

Our long term goal is to understand the regulation of monocyte/macrophage Fey receptor (FcyR) function and to apply this knowledge to enhance the efficacy of monoclonal antibody therapy for cancer. Macrophages are critical effector cells in antibody therapy, and their strength of response is governed by the ratio of activating to inhibiting FcyR and by intracellular phosphatases such as SHIP. We recently uncovered some additional and unexpected features of both FcyR and SHIP that significantly impact the responses of these cells to antibody-coated targets. Firstly, we discovered that the activating FcyRI and FcyRlla not only mediate different functions but are also subject to differential regulation by SHIP, with FcyRlla being more strongly suppressed. Secondly, we identified the GDP dissociation inhibitor LyGDI as a binding partner of SHIP and a regulator of FcyR function. Both SHIP and LyGDI are likely relevant clinically, as we found a significant upregulation of both in CLL patient monocytes compared to healthy age-matched controls. Importantly, because SHIP associates more strongly with FcyRlla than with FcyRI, upregulation of these molecules may prevent therapeutic antibodies, especially those engineered for stronger FcyRlla binding, from reaching their full functional potential. In efforts to reverse this suppressed phenotype, we discovered that certain Toll-like receptor (TLR) and Nodlike receptor (NLR) agonists could enhance FcyR function, thus providing potential therapeutic opportunities. In order to bridge the gap between these findings and improved treatment modalities, we need to fully elucidate the mechanism(s) behind this tumor-associated FcyR regulation and to test in depth the effects of these TLR/NLR agonists on monocyte/macrophage FcyR function. Thus, here we propose to test our hypothesis that monocyte / macrophage FcyR function is critically regulated by SHIP and its effector LyGDI, and that TLR and NLR agonists have the potential to reverse this regulation, thus permitting a more effective response during antibody therapy. In completing these studies we will have elucidated the mechanism of LyGDI effect on FcyR function tested promising methods of enhancing FcyR function both in vitro and in vivo, and examined the mechanism whereby tumor cells suppress monocyte FcyR function. We strongly believe that by pursuing these basic biological findings we will uncover clinically relevant ways to both overcome this immunosuppression and to optimize antibody-based treatments.

我们的长期目标是了解单核细胞/巨噬细胞FEY受体（FCYR）功能的调节，并应用这些知识以增强单克隆抗体治疗对癌症的疗效。巨噬细胞是抗体治疗中的关键效应细胞，其反应强度受激活与抑制FCYR和细胞内磷酸酶（例如船舶）的比率。最近，我们发现了FCYR和船舶的一些其他特征，这些特征会显着影响这些细胞对抗体涂层靶标的反应。首先，我们发现激活的FCYRI和FCYRLA不仅介导了不同的功能，而且还受到船舶的不同调节，而Fcyrlla受到了更严重的抑制。其次，我们将GDP解离抑制剂lygdi确定为船舶的结合伙伴和FCYR功能的调节剂。与健康年龄匹配的对照相比，我们发现CLL患者单核细胞中两者在CLL患者单核细胞中的显着上调，因此船舶和Lygdi都可能在临床上相关。重要的是，由于船只与FCYRLLA更强大的船与FCYRI相关，因此这些分子的上调可能会防止治疗性抗体，尤其是那些为更强的Fcyrlla结合而设计的抗体，无法达到其全部功能潜力。为了扭转这种抑制的表型，我们发现某些类似Toll样受体（TLR）和鼻状受体（NLR）激动剂可以增强FCYR功能，从而提供潜在的治疗机会。为了弥合这些发现与改善治疗方式之间的差距，我们需要充分阐明与肿瘤相关的FCYR调节背后的机制，并深入测试这些TLR/NLR激动剂对单核细胞/巨噬细胞FCYR功能的影响。因此，我们在这里提出了我们的假设，即单核细胞 /巨噬细胞FCYR功能受到船体及其效应子lygdi的严格调节，并且TLR和NLR激动剂有可能逆转这种调节，从而允许在抗体治疗期间产生更有效的反应。在完成这些研究时，我们将阐明Lygdi对FCYR效应的机制测试的有前途的方法，以增强体外和体内的FCYR功能，并检查了肿瘤细胞抑制单核细胞FCYR功能的机制。我们坚信，通过追求这些基本的生物学发现，我们将发现临床上相关的方法来克服这种免疫抑制并优化基于抗体的治疗方法。