Targeting the suppressive immune microenvironment in leptomeningeal melanoma metastases

针对软脑膜黑色素瘤转移中的抑制性免疫微环境

• 批准号: 10290150
• 负责人: Keiran Smalley
• 金额: $ 23.1万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290150
• 关键词: Address; Arachnoid Membrane; Beds; Behavior; Biology; Brain; CD8-Positive T-Lymphocytes; CSF1R gene; Cell Differentiation process; Cell physiology; Cells; Cellular Structures; Cerebrospinal Fluid; Clinical Trials; Combined Modality Therapy; Complication; Data; Disease Progression; Environment; Flow Cytometry; Frequencies; Future; Gene Expression Profiling; Goals; Grant; Immune; Immune checkpoint inhibitor; Immunity; Immunofluorescence Immunologic; Immunotherapy; Infiltration; Intrathecal Chemotherapy; Knowledge; Label; Leptomeningeal Melanoma; Leptomeninges; Lung; Mediating; Melanoma Cell; Metastatic Neoplasm to the Leptomeninges; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Patients; Pharmaceutical Preparations; Phase Ib Clinical Trial; Phenotype; Pia Mater; Play; Population; Radiation therapy; Regimen; Resistance; Role; Sampling; Series; Shapes; Signal Transduction; Skin; Specimen; T cell response; T-Lymphocyte; Testing; Time; Validation; adaptive immune response; anti-PD-1; anti-PD-L1; anti-tumor immune response; cell type; checkpoint inhibition; effective therapy; experimental study; immune checkpoint blockade; improved; improved outcome; in vivo; macrophage; melanoma; monocyte; mouse model; novel; novel strategies; novel therapeutic intervention; programmed cell death ligand 1; response; single-cell RNA sequencing; targeted treatment; treatment response; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions; virtual

Melanoma is a highly metastatic tumor, with a propensity to spread to the skin, lungs and brain. In ~5% of cases, patients also develop leptomeningeal melanoma metastases (LMM: e.g. melanoma cell infiltration into the pia mater, the arachnoid membranes and cerebrospinal fluid) which has a dismal survival of 8-10 weeks. There are no effective treatments for LMM. Understanding the biology of LMM in the context of drug response/resistance is a major unmet need. In preliminary studies, we used single cell RNA-Seq (scRNA-Seq) to identify a novel population of myeloid cells in samples of CSF from patients with LMM, which we believe suppress adaptive immune responses. We will test the hypothesis that myeloid cells in the LMM microenvironment are critical regulators of tumor progression and therapeutic response, and that the long-term management of LMM will require therapies that target both the melanoma cells and the immune-suppressive signals from the tumor microenvironment (TME). In Aim 1, we will use scRNA-Seq, flow cytometry and immunofluorescence to characterize the immune environment of CSF from patients with LMM, with a focus on the myeloid compartment. Functional studies will be undertaken to 1) determine the role of the CSF environment on myeloid cell differentiation 2) demonstrate that CSF-resident myeloid cells suppress T cell function. We will then interrogate serial CSF samples from our phase Ib clinical trial of patients with LMM to determine how inhibiting PD-L1 and radiation therapy shapes the myeloid and T cell repertoire of the CSF space. In Aim 2, we will define the role of myeloid cells in LMM progression in vivo. We will then perform in vivo experiments using mouse melanoma cells grown in the leptomeninges of C57/BL6 mice to determine if systemic or intrathecal inhibition of CCR2 and/or CSF1R sensitizes LMM to anti PD-1 in syngeneic mouse models of melanoma. We expect to define the immune environment of LMM and to develop the rationale for novel therapeutic strategies that can be rapidly evaluated in this most devastating complication of advanced melanom a.

黑色素瘤是一种高度转移性肿瘤，具有扩散到皮肤、肺和大脑的倾向。在约5%的 在一些病例中，患者还发生软脑膜黑素瘤转移（LMM：例如黑素瘤细胞浸润到脑膜中）。 软脑膜、蛛网膜和脑脊髓液），其生存期为8-10周。 对于LMM没有有效的治疗方法。在药物背景下了解LMM的生物学 反应/抗性是一个主要的未满足的需求。在初步研究中，我们使用单细胞RNA-Seq（scRNA-Seq） 在LMM患者的CSF样本中鉴定一种新的髓样细胞群，我们认为 抑制适应性免疫反应。我们将检验LMM中的髓样细胞 微环境是肿瘤进展和治疗反应的关键调节因子， LMM的管理将需要靶向黑色素瘤细胞和免疫抑制细胞两者的疗法。 肿瘤微环境（TME）。在目标1中，我们将使用scRNA-Seq、流式细胞术和流式细胞仪。 免疫荧光来表征LMM患者CSF的免疫环境，重点是 骨髓腔将进行功能研究，以1）确定CSF的作用 环境对骨髓细胞分化影响2）证明CSF驻留骨髓细胞抑制T细胞 功能然后，我们将询问来自LMM患者Ib期临床试验的系列CSF样本， 确定抑制PD-L1和放射治疗如何塑造CSF的骨髓和T细胞库 空间在目标2中，我们将定义髓样细胞在体内LMM进展中的作用。然后我们将在 使用在C57/BL 6小鼠的软脑膜中生长的小鼠黑素瘤细胞的体内实验，以确定 全身或鞘内抑制CCR 2和/或CSF 1 R使同基因小鼠中的LMM对抗PD-1敏感 黑色素瘤模型。我们期望定义LMM的免疫环境，并发展LMM的基本原理。 新的治疗策略，可以快速评估这种最具破坏性的并发症，先进的 梅拉诺姆河