Targeting TREM2 to boost anti-cancer therapy

靶向 TREM2 促进抗癌治疗

• 批准号: 10279674
• 负责人: MARCO COLONNA
• 金额: $ 41.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10279674
• 关键词: 3-Methylcholanthrene; Address; Adipose tissue; Alzheimer' s Disease; Alzheimer' 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; 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

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。免疫检查点疗法（ICT）最近的成功 革命性的肿瘤治疗，表明操纵免疫系统是治疗肿瘤的有效策略。 癌抑制CTLA-4和PD-1的MAb已广泛显示释放T细胞效应子功能， 控制小鼠和一些癌症患者的肿瘤。然而，ICT对某些肿瘤并不完全有效， 它们通过多种机制逃逸，其中之一是产生富含 免疫抑制骨髓细胞。TREM 2是一种由组织巨噬细胞表达的免疫受体， 通过ITAM途径，细胞内信号被传递。最近， TREM 2+巨噬细胞已在许多人类肿瘤中报道。在我们的初步数据中，我们证明， TREM 2缺陷或用mAb 178阻断小鼠TREM 2抑制了3-HT细胞的皮下肿瘤生长。 甲基胆蒽（MCA）细胞系，并导致完全肿瘤消退时，与次优 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 Trem 2-/-和抗TREM 2处理的小鼠中骨髓细胞景观的复杂重塑。的总目标 本申请旨在促进我们对TREM 2阻断在小鼠模型中的治疗作用的理解 和人类癌症。在目的1中，我们表明TREM 2靶向增强了由抗PD 1介导的ICT;我们提出 以确定TREM 2缺陷或阻断是否影响其他肿瘤疗法，如抗CTLA 4和 化疗，这会引发不同类型的免疫反应。TREM 2的影响将使用 注射的MCA细胞系和乳腺癌的自发MMTV-PyMT模型。在目标2中，我们将定义 抗TREM 2影响肿瘤微环境的机制。A.免疫抑制 巨噬细胞依赖于脂质代谢并积累脂滴; B）TREM 2促进泡沫细胞形成 c）抗TREM 2 mAb阻断脂质与TREM 2的结合，我们将检验以下假设： TREM 2阻断通过阻断脂质代谢将肿瘤巨噬细胞从免疫抑制性转化为免疫刺激性 液滴积聚和泡沫细胞形成。我们还将测试一种基于 观察到TREM 2被ADAM金属蛋白酶从细胞表面切割，产生可溶性TREM 2 （sTREM 2），其在各种疾病模型中促进巨噬细胞的存活。我们将检验这个假设， 在具有不可切割的TREM 2的转基因小鼠中缺乏sTREM 2阻止了免疫抑制性肿瘤的存活 巨噬细胞在目标3中，我们显示了未发表的数据，表明抗人TREM 2 mAb 21 E10延迟了肿瘤生长。 注射的MCA细胞系在表达人TREM 2代替小鼠TREM 2的小鼠中的生长。所以我们 将确定使用特异性mAb的TREM 2阻断是否可以扩展到临床前模型， 人类TREM 2受体总的来说，这一建议将推进我们对一种新的治疗方法的认识 基于TREM 2，拓宽了我们靶向肿瘤中免疫抑制性骨髓细胞的手段。