Enabling immunotherapy for high-risk Group 3 medulloblastoma via systems immunology

通过系统免疫学对高危 3 组髓母细胞瘤进行免疫治疗

基本信息

批准号：
10714138
负责人：
Hongbo Chi
金额：
$ 81.9万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-07 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714138
关键词：
Address Adoptive Cell Transfers Atlases Biology Brain Neoplasms CAR T cell therapy CD8-Positive T-Lymphocytes CRISPR screen Cancer Etiology Cell Communication Cell Therapy Cell physiology Cells Cellular biology Child Childhood Malignant Brain Tumor Classification Clustered Regularly Interspaced Short Palindromic Repeats Data Development Disease Exclusion Exhibits Genetic Genetically Engineered Mouse Genomics Goals Heterogeneity Human Immune Immune Evasion Immunocompetent Immunology Immunotherapeutic agent Immunotherapy Joints Macrophage Maps Mediating Modeling Molecular Multiomic Data Mus Network-based PTPRC gene Patients Phenotype Pre-Clinical Model Proteomics Refractory Resistance Reverse engineering Saint Jude Children&apos s Research Hospital Sampling Signal Transduction Sorting Subgroup System Systems Biology T cell response T cell therapy T-Lymphocyte TCF Transcription Factor Technology Testing Tumor Immunity Tumor stage Tumor-infiltrating immune cells Visualization cancer type childhood cancer mortality chimeric antigen receptor T cells clinically relevant cloud based data visualization disorder risk experimental study functional genomics high risk high risk population improved in vivo insight medulloblastoma mouse model multiple omics neoplastic cell nerve stem cell notch protein novel overexpression screening single cell analysis single-cell RNA sequencing spatiotemporal stem-like cell tool transcriptomic profiling transcriptomics tumor tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

PROJECT SUMMARY / ABSTRACT The goal of this project is to dissect the immune evasion mechanisms and enable immunotherapy for children with high-risk Group 3 medulloblastoma (G3MB) via systems immunology approaches. Brain tumors are the leading cause of cancer-related deaths in children. Medulloblastoma is the most prevalent malignant pediatric brain tumor and is characterized by four major molecular subgroups, among which G3MB is the most aggressive form and features MYC overexpression. The immunosuppressive tumor microenvironment (TME) is poorly understood in G3MB, and no immunotherapy is available for children with this high-risk disease. Systems immunology approaches—especially single-cell and spatial multi-omics profiling and in vivo CRISPR-based functional screening—have proven powerful in dissecting tumor–TME interactions and identifying novel immunotherapy targets in various cancer types, but very few studies have integrated these approaches. In our preliminary studies, we applied two unique immunocompetent genetically-engineered mouse models (GEMMs) of MYC-driven G3MB and performed scRNA-seq, scATAC-seq and spatial transcriptomics profiling. We enriched immune cells from the TME by sorting CD45 positive cells for single-cell studies. Our preliminary analysis of single-cell and spatial omics data revealed striking interactions of neural stem cell-like tumor cells with macrophages and other immune cells that potentially create a suppressive TME and drive immune evasion in mouse G3MB. We also performed in vivo CRISPR screening in tumor cells using the GEMMs to identify modulators of tumor development, which demonstrated the feasibility of in vivo functional genomics screening in our preclinical models. In this project, first, we propose to utilize cutting-edge single-cell and spatial omics technologies to characterize the two G3MB GEMMs at different stages of tumor progression. We will use our network-based tools to integrate these multi-omics data to dissect the dynamic tumor–immune interactions and underlying “hidden” drivers that drive the immune exclusion and suppression during G3MB progression. We will also validate discoveries of G3MB from mouse studies in patient samples. We will develop a cloud-based portal to visualize and explore our single-cell and spatial data and tumor–TME interactomes of G3MB. Second, we will establish the mechanistic basis of tumor–T cell interactions and strategies to enable adoptive T cell therapy for G3MB by discovering functional drivers and putative targets in both tumor cells and T cells. To this end, we will apply both candidate approach and in vivo CRISPR screening in immunocompetent GEMMs to identify tumor- intrinsic modulators that will remodel the suppressive TME and sensitize G3MB tumors to adoptive T cell and CAR-T cell therapies. We will also test if targeting inhibitory factors for T cell function will enable and optimize effective adoptive T cell therapies against such tumors. Our studies promise to provide new insights into mechanisms of tumor–TME interactions in G3MB and manifest legitimate immunotherapeutic opportunities.

项目概要/摘要该项目的目标是剖析免疫逃避机制并为儿童提供免疫治疗通过系统免疫学方法治疗高危 3 类髓母细胞瘤 (G3MB) 是脑肿瘤的主要治疗方法。髓母细胞瘤是儿童癌症相关死亡的主要原因。脑肿瘤，具有四个主要分子亚群的特征，其中 G3MB 是最具侵袭性的 MYC 过度表达的形式和特征免疫抑制肿瘤微环境 (TME) 较差。 G3MB 已被了解，并且对于患有这种高风险疾病的儿童没有可用的免疫疗法。免疫学方法——尤其是单细胞和空间多组学分析以及基于 CRISPR 的体内功能筛选——已被证明在剖析肿瘤与 TME 相互作用和识别新的免疫疗法针对各种癌症类型，但很少有研究将这些方法整合到我们的研究中。初步研究中，我们应用了两种独特的免疫活性基因工程小鼠模型（GEMM）我们对 MYC 驱动的 G3MB 进行了 scRNA-seq、scATAC-seq 和空间转录组学分析。我们对来自 TME 的免疫细胞进行了分选 CD45 阳性细胞进行单细胞研究。单细胞和空间组学数据揭示了神经干细胞样肿瘤细胞与巨噬细胞和其他免疫细胞可能会产生抑制性 TME 并驱动免疫逃避我们还使用 GEMM 在肿瘤细胞中进行了体内 CRISPR 筛选以鉴定肿瘤发展的调节剂，证明了体内功能基因组学筛选的可行性在我们的临床前模型中，首先，我们建议利用尖端的单细胞和空间组学。我们将使用我们的技术来表征肿瘤进展不同阶段的两种 G3MB GEMM。基于网络的工具来整合这些多组学数据来剖析动态肿瘤免疫相互作用在 G3MB 进展过程中驱动免疫排斥和抑制的潜在“隐藏”驱动因素。还验证了小鼠研究中 G3MB 的发现。我们将开发一个基于云的门户。其次，我们将可视化和探索我们的单细胞和空间数据以及 G3MB 的肿瘤-TME 相互作用组。建立肿瘤与 T 细胞相互作用的机制基础和策略，以实现过继性 T 细胞治疗 G3MB 通过发现肿瘤细胞和 T 细胞中的功能驱动因素和假定靶点，我们将实现这一目标。在免疫活性 GEMM 中应用候选方法和体内 CRISPR 筛选来识别肿瘤内在调节剂将重塑抑制性 TME 并使 G3MB 肿瘤对过继性 T 细胞敏感我们还将测试针对 T 细胞功能的抑制因子是否能够实现和优化。针对此类肿瘤的有效过继 T 细胞疗法有望提供新的见解。 G3MB 中肿瘤与 TME 相互作用的机制并显示出合法的免疫治疗机会。