Defining mechanisms to promote antitumor immunity by modulating one-carbon metabolism

定义通过调节一碳代谢促进抗肿瘤免疫的机制

基本信息

批准号：
10565099
负责人：
Nathalie YR Agar
金额：
$ 58.01万
依托单位：
HARVARD MEDICAL SCHOOL
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：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565099
关键词：
ATAC-seq Affect Anabolism Antigens Atlases CD8-Positive T-Lymphocytes Carbon Cell physiology Cells Chromatin Clustered Regularly Interspaced Short Palindromic Repeats Coculture Techniques Data Effectiveness Effector Cell Enzymes Epigenetic Process Formates Gene Expression Profile Genes Genetic Genetic Transcription Glucose Glutathione Glycine Goals Heterogeneity Immune Immune response Immune system Immunofluorescence Immunologic Immunotherapy In Vitro Individual Intercellular Fluid Knockout Mice Ligands Malignant Neoplasms Mass Spectrum Analysis Mediating Memory Metabolic Metabolic Pathway Metabolism Methionine Modeling Molecular Mus NADP Nucleotides Outcome PD-1 blockade Pathway interactions Periodicity Population Purines Resolution Role Serine Source Supplementation System T cell response T-Cell Activation T-Lymphocyte Testing Tumor Immunity anti-PD-1 anti-PD1 therapy anti-tumor immune response cancer cell cancer immunotherapy cancer therapy conditional knockout cytotoxic effector T cell exhaust genetic approach immune checkpoint blockade immune function improved in vivo innovation melanoma metabolic fitness metabolic profile metabolomics neoplastic cell new therapeutic target novel patient subsets prevent programmed cell death ligand 1 programmed cell death protein 1 programs response single-cell RNA sequencing synergism tumor tumor growth tumor microenvironment tumor progression

项目摘要

Immune checkpoint blockade (ICB) targeting PD-1 and its ligand PD-L1 has revolutionized cancer therapy, but only a subset of patients respond, highlighting the critical need to investigate mechanisms of anti-tumor immunity to identify novel targets to enhance the effects of ICB. The goal of this project is to determine mechanisms by which one-carbon (1C) metabolism can be modulated to improve the efficacy of PD-1 blockade. We recently identified 1C metabolism, which allows cells to utilize serine or glycine to generate 1C units for nucleotides, NADPH, and glutathione biosynthesis, as the most induced metabolic pathway during T cell activation. We also discovered that there are deficits in serine and glucose levels in the tumor microenvironment (TME). Strikingly, restoring 1C metabolism by formate supplementation increases the effectiveness of anti-PD-1 treatment and tumor clearance in mouse tumor models. We hypothesize that 1C metabolism is limiting for anti-tumor T cell function and that increasing this pathway by formate supplementation can synergize with ICB to promote anti-tumor immunity. We will test this hypothesis in two aims: Aim 1: Determine cellular and molecular mechanisms by which formate supplementation improves the efficacy of PD-1 mediated tumor clearance. We will define transcriptional and epigenetic mechanisms by which 1C metabolism and formate supplementation improve CD8+ T cell function and synergize with PD-1 blockade. We will use innovative conditional knockout models and in vivo genetic perturbation studies to delete rate- limiting enzymes of 1C metabolism in CD8+ T cells, and analyze their impact on response to PD- 1 blockade. Aim 2: Determine metabolic mechanisms by which formate supplementation improves the efficacy of PD-1 mediated tumor clearance. We will use cellular and in vivo mass spectrometry-based metabolite tracing studies, and spatial metabolomics to elucidate how formate supplementation and modulation of 1C metabolism impact metabolic profiles of anti- tumor CD8+ T cells when combined with anti-PD-1. These studies will provide us with the first spatial and single cell resolution atlas of metabolic and functional immune responses in a tumor in response to ICB. We will determine how formate supplementation improves CD8+ T cell responses from the level of individual CD8+ T cells to CD8+ T cells in the metabolically heterogenous TME. Completion of these studies will be transformative by changing the paradigm of 1C metabolism in cancer treatment and demonstrating that supplementing 1C units can enhance anti-tumor immunity. Our results will inform strategies and identify novel therapeutic targets for improving cancer immunotherapy outcomes.

靶向PD-1及其配体PD-L1的免疫检查点封锁（ICB）彻底改变了癌症治疗，但只有一部分患者反应，强调了调查的关键需求抗肿瘤免疫的机理，以鉴定新靶标，以增强ICB的影响。这该项目的目标是确定一个碳（1C）代谢的机制调节以提高PD-1阻滞的功效。我们最近确定了1C代谢，这是允许细胞利用丝氨酸或甘氨酸生成核苷酸，NADPH和谷胱甘肽生物合成，作为T细胞活化过程中最诱导的代谢途径。我们也是发现肿瘤微环境中的丝氨酸和葡萄糖水平缺陷（TME）。令人惊讶的是，通过补充构造恢复1C代谢增加了抗PD-1治疗和肿瘤清除率在小鼠肿瘤模型中的有效性。我们假设1C代谢限制了抗肿瘤T细胞功能的限制，并且增加了这一点补充甲酸盐的途径可以与ICB协同以促进抗肿瘤免疫。我们将在两个目的中检验这一假设：目标1：确定细胞和分子机制构造补充剂可提高PD-1介导的肿瘤清除率的功效。我们将定义转录和表观遗传机制，通过1C代谢和甲酸补充改善了CD8+ T细胞功能，并与PD-1阻滞协同作用。我们将使用创新的条件敲除模型和体内遗传扰动研究以删除速率 - 限制CD8+ T细胞中1C代谢的酶，并分析其对PD-反应的影响 1个封锁。目标2：确定构造补充的代谢机制提高PD-1介导的肿瘤清除率的功效。我们将使用细胞和体内质量基于光谱法的代谢物追踪研究和空间代谢组学以阐明如何 1C代谢的甲酸盐补充和调节影响抗抗代谢谱与抗PD-1结合时，肿瘤CD8+ T细胞。这些研究将为我们提供第一个肿瘤中代谢和功能免疫反应的空间和单细胞分辨率响应ICB。我们将确定甲酸盐补充如何改善CD8+ T细胞从代谢中，从单个CD8+ T细胞水平到CD8+ T细胞的响应异源TME。这些研究的完成将通过更改范式进行变革癌症治疗中的1C代谢，并证明补充1C单位可以增强抗肿瘤免疫力。我们的结果将为策略提供信息，并确定新颖的治疗性改善癌症免疫疗法结局的靶标。