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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：
10456946
负责人：
Keiran Smalley
金额：
$ 18.86万
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/10456946
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 antagonist anti-PD-1 anti-PD-L1 anti-tumor immune response cell type checkpoint inhibition checkpoint therapy 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。占~5%

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease.

DOI：
10.3791/62033
发表时间：
2021-01-29
期刊：
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
影响因子：
1.2
作者：
Law, Vincent;Baldwin, Margi;Ramamoorthi, Ganesan;Kodumudi, Krithika;Nam Tran;Smalley, Inna;Duckett, Derek;Kalinski, Pawel;Czerniecki, Brian;Smalley, Keiran S. M.;Forsyth, Peter A.
通讯作者：
Forsyth, Peter A.