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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.

项目概要癌症是死亡和疾病的主要原因。免疫检查点疗法（ICT）最近取得的成功彻底改变了肿瘤治疗，表明操纵免疫系统是治疗肿瘤的有效策略癌症。抑制 CTLA-4 和 PD-1 的单克隆抗体已被广泛证明可以释放 T 细胞效应功能，控制小鼠和一些癌症患者的肿瘤。然而，ICT对于某些肿瘤并不完全有效，它使用多种机制逃脱，其中之一是产生富含免疫抑制性骨髓细胞。 TREM2 是一种由组织巨噬细胞表达的免疫受体，可结合磷脂和脂蛋白并通过 ITAM 途径传递细胞内信号。最近，据报道，TREM2+巨噬细胞存在于许多人类肿瘤中。在我们的初步数据中，我们证明 TREM2 缺陷或使用 mAb 178 阻断小鼠 TREM2 可抑制 3- 的皮下肿瘤生长甲基胆蒽 (MCA) 细胞系，当与次优相关时导致肿瘤完全消退 PD-1免疫疗法。此外，对 MCA 模型中肿瘤细胞浸润的高分辨率分析表明 Trem2–/– 和抗 TREM2 治疗小鼠骨髓细胞景观的复杂重塑。总体目标为该应用旨在加深我们对 TREM2 阻断在小鼠模型中的治疗影响的理解和人类癌症。在目标 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 缺陷或阻断是否影响其他肿瘤治疗，例如抗 CTLA4 和化疗，引起不同类型的免疫反应。 TREM2 的影响将通过以下方式进行评估：注射的 MCA 细胞系和自发的乳腺癌 MMTV-PyMT 模型。在目标 2 中，我们将定义抗 TREM2 影响肿瘤微环境的机制。鉴于 a) 免疫抑制巨噬细胞依赖脂质代谢并积累脂滴； b) TREM2促进泡沫细胞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阻断通过阻断脂质将肿瘤巨噬细胞从免疫抑制转变为免疫刺激液滴积累和泡沫细胞形成。我们还将测试基于的替代机制观察到 TREM2 被 ADAM 金属蛋白酶从细胞表面裂解，生成可溶性 TREM2 (sTREM2)，可促进各种疾病模型中巨噬细胞的存活。我们将检验以下假设：具有不可切割 TREM2 的转基因小鼠中缺乏 sTREM2 可阻止免疫抑制肿瘤的存活巨噬细胞。在目标 3 中，我们展示了未发表的数据，表明抗人 TREM2 mAb 21E10 可以延缓肿瘤发生注射的 MCA 细胞系在表达人 TREM2 代替小鼠 TREM2 的小鼠中生长。因此，我们将确定使用特定 mAb 的 TREM2 阻断是否可以扩展到表达的临床前模型人类 TREM2 受体。总体而言，该提案将增进我们对新型治疗方法的了解基于 TREM2，它拓宽了我们针对肿瘤中免疫抑制性骨髓细胞的武器库。