Targeting TREM2 to boost anti-cancer therapy

靶向 TREM2 促进抗癌治疗

基本信息

批准号：
10477296
负责人：
MARCO COLONNA
金额：
$ 43.23万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10477296
关键词：
3-Methylcholanthrene Address Adipose tissue Alzheimer&apos s Disease Alzheimer&apos s disease model Appearance Applications Grants Arterial Fatty Streak Attention Awards and Prizes Binding Blocking Antibodies Breast Cancer Model CTLA4 gene Cancer Patient Cancer cell line Catabolism Cause of Death Cell Line Cell surface Cessation of life Cholesterol Cholesterol Esters Chronic Cleaved cell Colorectal Complement Complex Data Defect Diagnosis Disease Disease model Fibrosis Foam Cells Generations Genes Genetic study Goals High Fat Diet Host Defense Human ITAM Immune Immune response Immune system Immunologic Receptors Immunosuppression Immunotherapy Knowledge Lipid Binding Lipids Lipoprotein Binding Lipoproteins Lung MC38 Malignant Neoplasms Mediating Metabolism Metalloproteases Methylcholanthrene Microglia Modeling Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Nobel Prize Oncology Pathway interactions Patients Peripheral Phospholipids Population Pre-Clinical Model Process Reporting Resolution Risk Factors Senile Plaques Signal Transduction Subcutaneous Injections TREM2 gene Testing Therapeutic Tissues Transgenic Mice Tumor-infiltrating immune cells United States Variant Virus Diseases anti-CTLA4 anti-PD-1 antitumor effect base cancer immunotherapy cancer therapy carcinogenesis checkpoint therapy chemotherapy chronic inflammatory disease effector T cell humanized mouse immune checkpoint blockade immunosuppressive macrophages improved inhibiting antibody lipid metabolism macrophage malignant breast neoplasm mouse model neoplastic cell novel therapeutic intervention patient subsets prevent programmed cell death protein 1 receptor response standard care subcutaneous success targeted cancer therapy tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY Cancer is a leading cause of death and disease. The recent success of immune checkpoint therapy (ICT) has revolutionized tumor therapy, indicating that manipulation of the immune system is an effective strategy to treat cancer. MAbs inhibiting CTLA-4 and PD-1 have been extensively shown to unleash T cell effector functions to control tumors in both mice and some cancer patients. However, ICT is incompletely effective for certain tumors, which escape using multiple mechanisms, one of which is the generation of a tumor microenvironment rich in immunosuppressive myeloid cells. TREM2 is an immune receptor expressed by tissue macrophages that binds phospholipids and lipoproteins and transmits intracellular signals through the ITAM pathway. Recently, TREM2+ macrophages have been reported in many human tumors. In our preliminary data, we demonstrate that TREM2-deficiency or mouse TREM2 blockade with the mAb 178 curbs subcutaneous tumor growth of the 3- methylcholanthrene (MCA) cell line and leads to complete tumor regression when associated with suboptimal PD-1 immunotherapy. Furthermore, high-resolution analysis of the tumor cell infiltrate in the MCA model reveals complex remodeling of the myeloid cell landscape in Trem2–/– and anti-TREM2 treated mice. The overall goal of this application is to advance our understanding of the therapeutic impact of TREM2 blockade in mouse models and human cancer. In Aim 1 we show that TREM2 targeting enhances ICT mediated by anti-PD1; we propose to determine whether TREM2 deficiency or blockade impact other tumor therapies, such as anti-CTLA4 and chemotherapy, which elicit different types of immune responses. The impact of TREM2 will be assessed using injected MCA cell lines and the spontaneous MMTV-PyMT model of breast cancer. In Aim 2 we will define the mechanisms through which anti-TREM2 impacts the tumor microenvironment. Given that a) immunosuppressive macrophages depend on lipid metabolism and accumulate lipid droplets; b) TREM2 promotes foam cell formation by binding lipoproteins; and c) anti-TREM2 mAb blocks lipid binding to TREM2, we will test the hypothesis that TREM2 blockade converts tumor macrophages from immunosuppressive to immunostimulatory by blocking lipid droplet accumulation and foam cell formation. We will also test an alternative mechanism based on the observation that TREM2 is cleaved from the cell surface by ADAM metalloproteases, generating soluble TREM2 (sTREM2), which promotes survival of macrophages in various disease models. We will test the hypothesis that lack of sTREM2 in a transgenic mouse with uncleavable TREM2 prevents survival of immunosuppressive tumor macrophages. In Aim 3, we show unpublished data indicating that anti-human TREM2 mAb 21E10 delays tumor growth of an injected MCA cell line in mice expressing human TREM2 in place of mouse TREM2. Therefore, we will determine whether TREM2 blockade with a specific mAb can be extended to a preclinical model expressing the human TREM2 receptor. Overall, this proposal will advance our knowledge of a novel therapeutic approach based on TREM2 that broadens our armamentarium for targeting immunosuppressive myeloid cells in tumors.

项目摘要癌症是死亡和疾病的主要原因。免疫切除点疗法（ICT）的最新成功已有革命性的肿瘤疗法，表明对免疫系统的操纵是治疗的有效策略癌症。抑制CTLA-4和PD-1的mAB已广泛证明，将T细胞效应子函数释放到控制小鼠和某些癌症患者的肿瘤。但是，ICT对某些肿瘤不完全有效，使用多种机制逃脱，其中之一是富含肿瘤微环境的产生免疫抑制髓样细胞。 TREM2是由结合的组织巨噬细胞表达的免疫接收器磷脂和脂蛋白和脂蛋白通过ITAM途径传输细胞内信号。最近，在许多人类肿瘤中已经报道了TREM2+巨噬细胞。在我们的初步数据中，我们证明了 Trem2缺乏或小鼠Trem2阻断了3--的MAB 178曲线皮下肿瘤生长甲基胆碱（MCA）细胞系，并导致与次优相关时肿瘤回归 PD-1免疫疗法。此外，MCA模型中肿瘤细胞浸润的高分辨率分析揭示了在TREM2 - / - 和抗Trem2处理的小鼠中对髓样细胞景观进行复合重塑。总体目标该应用是为了促进我们对鼠标模型中TREM2封锁的治疗影响的理解和人类癌。在AIM 1中，我们表明TREM2靶向增强了抗PD1介导的ICT；我们建议确定TREM2缺乏或阻断是否会影响其他肿瘤疗法，例如抗CTLA4和化学疗法，引起不同类型的免疫复杂。 trem2的影响将使用注射MCA细胞系和乳腺癌的赞助MMTV-PYMT模型。在AIM 2中，我们将定义抗Trem2影响肿瘤微环境的机制。鉴于a）免疫抑制巨噬细胞取决于脂质代谢和丙烯酸脂质液滴。 b）TREM2促进泡沫细胞的形成通过结合脂蛋白； c）抗Trem2 mAb阻断脂质与Trem2的结合，我们将检验以下假设。 TREM2封锁通过阻断脂质将肿瘤巨噬细胞从免疫抑制转化为免疫刺激性液滴积累和泡沫细胞形成。我们还将测试基于观察到trem2通过亚当金属蛋白酶从细胞表面裂解，产生固体trem2 （Strem2），它促进了各种疾病模型中巨噬细胞的存活。我们将检验以下假设具有不可泄漏的TREM2的转基因小鼠中缺乏streem2可防止免疫抑制肿瘤的存活巨噬细胞。在AIM 3中，我们显示了未发表的数据，表明抗人类TREM2 MAB 2 21E10延迟肿瘤在表达人trem2的小鼠中注射的MCA细胞系的生长代替小鼠trem2。因此，我们将确定是否可以将具有特定MAB的Trem2阻断扩展到表达的临床前模型人类TREM2受体。总体而言，该建议将提高我们对一种新型治疗方法的了解基于TREM2，它扩大了我们的arammentarium，以靶向肿瘤中的免疫抑制髓样细胞。