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

基本信息

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
项目类别：
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

项目摘要

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的肿瘤，有扩散到皮肤、肺部和大脑的倾向。约 5% 在某些情况下，患者还会出现软脑膜黑色素瘤转移（LMM：例如黑色素瘤细胞浸润到软脑膜、蛛网膜和脑脊液），其存活时间仅为 8-10 周。 LMM 没有有效的治疗方法。了解药物背景下 LMM 的生物学响应/抵抗是一个未满足的主要需求。在初步研究中，我们使用单细胞RNA-Seq (scRNA-Seq) 鉴定 LMM 患者脑脊液样本中的新骨髓细胞群，我们认为抑制适应性免疫反应。我们将检验 LMM 中的骨髓细胞这一假设微环境是肿瘤进展和治疗反应的关键调节因素，长期来看 LMM 的治疗需要针对黑色素瘤细胞和免疫抑制细胞的治疗来自肿瘤微环境（TME）的信号。在目标 1 中，我们将使用 scRNA-Seq、流式细胞术和免疫荧光来表征 LMM 患者脑脊液的免疫环境，重点是骨髓室。将进行功能研究以 1) 确定 CSF 的作用环境对骨髓细胞分化的影响 2) 证明脑脊液驻留的骨髓细胞抑制 T 细胞功能。然后，我们将询问来自 LMM 患者的 Ib 期临床试验的系列脑脊液样本，以确定抑制 PD-L1 和放射治疗如何塑造 CSF 的骨髓细胞和 T 细胞库空间。在目标 2 中，我们将定义骨髓细胞在体内 LMM 进展中的作用。然后我们将在使用在 C57/BL6 小鼠软脑膜中生长的小鼠黑色素瘤细胞进行体内实验，以确定是否在同系小鼠中全身或鞘内抑制 CCR2 和/或 CSF1R 使 LMM 对抗 PD-1 敏感黑色素瘤模型。我们期望定义 LMM 的免疫环境并发展其基本原理可以在这种最具破坏性的晚期并发症中快速评估的新颖治疗策略黑素A.