Targeting TREM2 to boost anti-cancer therapy

项目总结 癌症是导致死亡和疾病的主要原因。最近免疫检查点治疗(ICT)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 癌症。抑制CTLA-4和PD-1的单抗被广泛证明可以释放T细胞效应器功能 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脱，其中之一是产生富含 免疫抑制的髓系细胞。TREM2是一种免疫受体，由组织巨噬细胞表达，结合 磷脂和脂蛋白，并通过ITAM途径传递细胞内信号。最近， TREM2巨噬细胞在许多人类肿瘤中已有报道。在我们的初步数据中，我们证明 TREM2缺乏或用单抗178阻断小鼠TREM2抑制皮下肿瘤生长3- 并导致肿瘤完全消退，当与次优联合使用时 PD-1免疫治疗。此外，对MCA模型中肿瘤细胞浸润物的高分辨率分析揭示了 经TREM2-/-和抗TREM2基因治疗的小鼠髓系细胞形态的复杂重塑。的总目标是 这一应用旨在促进我们对TREM2阻断在小鼠模型中的治疗作用的理解 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；我们提出 确定TREM2缺乏或阻断是否影响其他肿瘤治疗，如抗CTLA4和 化疗，它会引起不同类型的免疫反应。将使用以下方法评估TREM2的影响 注射MCA细胞系和自发性MMTV-PYMT乳腺癌模型。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 巨噬细胞依赖脂类代谢并积累脂滴；b)TREM2促进泡沫细胞的形成 通过结合脂蛋白；以及c)抗TREM2单抗阻断脂类与TREM2的结合，我们将检验这一假设 TREM2阻断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 液滴堆积和泡沫细胞形成。我们还将测试一种基于 观察到TREM2被ADAM金属蛋白酶从细胞表面切割，产生可溶性TREM2 (STREM2)，在各种疾病模型中促进巨噬细胞的存活。我们将检验这一假设 携带不可切割TREM2的转基因小鼠缺乏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单抗21E10延缓肿瘤 表达人TREM2的MCA细胞系在小鼠体内的生长。因此，我们 将确定用特定单抗阻断TREM2是否可以扩展到临床前模型表达 人类的TREM2受体。总体而言，这项建议将促进我们对一种新的治疗方法的了解 基于TREM2，扩大了我们针对肿瘤中免疫抑制髓系细胞的武器。

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.