Immune activation by necroptotic cell death

坏死性细胞死亡激活免疫

基本信息

批准号：
10318967
负责人：
Andrew Atwell Oberst
金额：
$ 40.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-15 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318967
关键词：
Adaptive Immune System Antigen-Presenting Cells Antigens Apoptosis Apoptotic Autoimmunity Automobile Driving Biology Brain Cell Death Cells Cessation of life Clinic Couples Data Dendritic Cells Development Engineering Environment Event Flow Cytometry Genetic Transcription Goals Homeostasis Immune Immune checkpoint inhibitor Immune response Immune system Immunotherapy Infection Inflammation Inflammatory Response Lead Lytic Malignant Neoplasms Modeling Molecular NF-kappa B Nature Necrosis Neoplasm Metastasis Neoplasm Transplantation Pattern Phagocytes Phosphotransferases Production Property Protein Kinase RIPK1 gene Reporting Rupture Signal Pathway Site Swelling System T-Lymphocyte Testing Tissues Transplantation Tumor Antigens Tumor Immunity Tumor-Derived Viral Virus Diseases Work adaptive immune response adaptive immunity anti-tumor immune response cancer cell cell suicide cell transformation chemokine clinically relevant completed suicide cytotoxic experimental study human disease imaging approach immune activation immune clearance immunogenic immunogenic cell death immunogenicity improved in vivo insight lymph nodes neoplasm immunotherapy neoplastic cell novel particle pathogen prevent programs prostate cancer model reagent testing receptor function recruit response tumor tumor microenvironment uptake

项目摘要

Programmed cell death is required for normal development and tissue homeostasis, but can also occur as a defensive response to pathogen infection. We now understand that cells can undergo distinct forms of programmed cell death: in addition to apoptosis, necroptosis is a recently-described form of cell suicide that can be induced by viral infection. Necroptosis involves cellular swelling and rupture, and has been hypothesized to trigger inflammatory and immune responses when it occurs in vivo, but the determinants of immune responses to necroptosis are not well understood. We have found that activation of the key necroptosis-inducing kinase, RIPK3, can trigger transcriptional responses in addition to inducing cell death. Furthermore, our preliminary data indicate that chemokine expression induced by RIPK3 activation accompanies RIPK3-induced cell death, and that this transcriptional response is required to render necroptosis immunogenic. This leads to the central hypothesis of this proposal: That necroptosis represents a uniquely immunogenic form of cell death, because it couples the production if immune-attractant chemokines with lytic cell death. An important extension of this idea, which we will test, is that induction of necroptosis within the tumor microenvironment will promote beneficial tumor immunity. To test this idea, we will focus on three Aims. First, we will use novel high-content imaging approaches to compare the way the immune system traffics, presents, and reacts to antigens derived from apoptotic, necroptotic, or necrotic cells. We will then use flank tumor models, in combination with a newly developed system for the rapid induction of different forms of cell death in vivo, assess the immune response to the necroptotic death of tumor cells. We will apply these findings to clinically-relevant tumor models, by testing the ability of the immune signature created by tumor cell necroptosis to synergize with immune checkpoint inhibitors and to promote immune clearance of metastatic lesions. Finally, we will create and test a system allowing rapid induction of necroptosis in unmodified tumor cells in vivo. Together, the experiments proposed here will determine what makes necroptosis immunogenic, then apply these findings to models of tumor immunotherapy.

正常发育和组织稳态需要编程的细胞死亡，但也可以作为一个对病原体感染的防御反应。我们现在知道，细胞可以经历不同的形式程序性细胞死亡：除凋亡外，坏死是最近描述的细胞自杀形式可以通过病毒感染诱导。坏死性涉及细胞肿胀和破裂，已经是假设在体内发生时会引发炎症和免疫反应，但是对坏死性的免疫反应尚不清楚。我们发现钥匙的激活坏死性诱导激酶RIPK3还可以触发转录反应，而诱导细胞死亡。此外，我们的初步数据表明RIPK3激活诱导的趋化因子表达伴随RIPK3诱导的细胞死亡，并且需要这种转录反应才能导致坏死作用免疫原性。这导致了该提议的中心假设：坏死性代表了一个独特的细胞死亡的免疫原性形式，因为如果免疫吸引趋化因子，它将其伴随裂解细胞死亡。我们将测试的这个想法的重要扩展是诱导坏死性在肿瘤微环境中，将促进有益的肿瘤免疫力。为了测试这个想法，我们将专注于三个目标。首先，我们将使用新颖的高含有成像方法来比较免疫系统运输，呈现和对源自凋亡，坏死或坏死细胞的抗原的反应。然后，我们将使用侧面肿瘤模型，并结合新开发的系统快速诱导体内不同形式的细胞死亡，评估对肿瘤细胞坏死死亡的免疫反应。我们通过测试免疫特征的能力，将把这些发现应用于临床上相关的肿瘤模型由肿瘤细胞坏死性创建，与免疫检查点抑制剂协同作用并促进免疫转移性病变的清除。最后，我们将创建和测试一个允许快速诱导坏死的系统在体内未修饰的肿瘤细胞中。一起，这里提出的实验将决定什么使坏死性免疫原性，然后将这些发现应用于肿瘤免疫疗法模型。