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Metabolic regulation of the anti-tumor CD8+ T cell response to PD-1 by asparagine

天冬酰胺对抗肿瘤 CD8 T 细胞对 PD-1 反应的代谢调节

基本信息

批准号：
10672044
负责人：
Peter Georgiev
金额：
$ 4.44万
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：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672044
关键词：
Acceleration Adoptive Transfer Asparagine Aspartate Aspartate-Ammonia Ligase Biological Response Modifiers Blocking Antibodies CD8-Positive T-Lymphocytes CRISPR screen CRISPR/Cas technology Cancer Patient Carbon Cell physiology Cells Cellular Immunology Chronic Clinical Coculture Techniques Combined Modality Therapy Cytotoxic T-Lymphocytes Development Disease remission Dissociation Enzymes Genes Glutamine Goals Immune Evasion Immune Tolerance Immune system Immunity Immunologic Receptors Immunologics Impairment In Vitro Infusion procedures Intervention Isotope Labeling Knowledge Label Ligands Link Lymphocyte Maintenance Mediating Metabolic Metabolic Pathway Metabolism Monoclonal Antibodies Mus Nitrogen Nutrient Pathway interactions Patients Peripheral Play Proliferating Property Protein Biosynthesis Proteins Regulation Research Resistance Resistance development Role Supplementation System T cell response T-Cell Activation T-Lymphocyte Techniques Testing Therapeutic Translating Tumor Immunity Validation anti-PD-1 anti-PD1 therapy asparaginase cancer clinical trial cancer type combinatorial cytotoxic exhaust exhaustion experimental study extracellular functional genomics immune activation immune checkpoint immune checkpoint blockade immunopathology improved in vivo loss of function neoplastic cell novel novel strategies pathogen patient subsets pharmacologic progenitor programmed cell death ligand 1 programmed cell death protein 1 response stem success synergism tumor tumor growth tumor microenvironment uptake

项目摘要

Abstract The T cell co-inhibitory checkpoint programmed cell death 1 (PD-1) plays a critical role in the maintenance of peripheral immunological tolerance. However the PD-1 pathway can be co-opted by chronic pathogens and tumor cells to promote immune evasion. Immune checkpoint blockade (ICB) using antibodies that block the PD- 1/PD-L1 ligand interactions have demonstrated remarkable success in cancer clinical trials. Despite inducing durable responses in a subset of patients, most patients do not develop stable remission after therapy. Therefore, it is critical to understand the immunological and cellular features associated with response and resistance to ICB. Metabolic remodeling is intrinsically linked to the development, differentiation and activation of immune cells, including anti-tumor T cells. Yet, little is known about the metabolic vulnerabilities of anti-tumor T cells, including metabolic pathways that govern the reinvigoration of exhausted anti-tumor T cells during ICB therapy. Our preliminary studies identified asparagine synthetase (Asns) as a novel metabolic regulator of the anti- tumor CD8+ T cell response to anti-PD-1 therapy and provided evidence for a central role for asparagine metabolism in regulating the efficacy of anti-PD-1 treatment in CD8+ T cell-mediated control of tumors. We will test this hypothesis in two aims: 1) Define the metabolic pathway(s) regulated by asparagine metabolism in anti- tumor CD8+ T cells and 2) Determine the role of asparagine metabolism in regulating CD8+ T cell exhaustion in- vivo during PD-1 blockade. In Aim 1 we will systematically determine the metabolic mechanism(s) by which asparagine regulates CD8+ T cells by comparing wild-type and CRISPR/Cas9-edited Asns-/- anti-tumor CD8+ T cells. The fate(s) and contribution(s) of asparagine to distinct metabolic pathways, protein synthesis, and cytolytic T cell activity will be assessed using isotopically labeled forms of asparagine, aspartate and glutamine in a novel co-culture system with T cells and tumor cells. Aim 2 will comprehensively interrogate the roles of asparagine metabolism, including asparagine synthesis and uptake, by leveraging functional genomic perturbation approaches to target asparagine synthetase and the asparagine transporter SLC15A in exhausted CD8+ T cells during anti-PD-1 treatment in tumor bearing-mice. Combinatorial approaches in which asparagine is supplemented or pharmacologically depleted will reveal how modulation of this pathway regulates anti-tumor T cell function and synergizes with ICB. Our research is conceptually novel and will address an important gap in our understanding of metabolic circuits critical for the maintenance and functional responses of exhausted anti-tumor CD8+ T cells during anti- PD-1 therapy. Since little is known about metabolic pathway usage and vulnerabilities of T cells within a nutrient limited tumor microenvironment, the identification and successful validation of asparagine metabolism as a central metabolic node that regulates anti-PD-1 efficacy may ultimately enable novel clinical strategies to improve the clinical response to ICB therapy by providing metabolic support to T cells.

摘要 T细胞共抑制检查点程序性细胞死亡1(PD-1)在维持外周免疫耐受。然而，PD-1途径可以被慢性病原体和肿瘤细胞促进免疫逃避。免疫检查点阻断(ICB)使用抗体阻断PD- 1/PD-L1配体相互作用在癌症临床试验中显示出显著的成功。尽管诱人持久反应在一部分患者中，大多数患者在治疗后不会出现稳定的缓解。因此，了解与免疫应答和抗药性相关的免疫学和细胞学特征是至关重要的。 ICB。代谢重塑与免疫的发育、分化和激活有着内在的联系细胞，包括抗肿瘤T细胞。然而，人们对抗肿瘤T细胞的代谢脆弱性知之甚少。包括控制ICB治疗期间耗尽的抗肿瘤T细胞恢复活力的代谢途径。我们的初步研究证实天冬酰胺合成酶(ASNS)是一种新的抗心磷脂抗体的代谢调节剂。肿瘤CD8+T细胞对抗PD-1治疗的反应及天冬酰胺发挥中枢作用的证据代谢调节抗PD-1治疗在CD8+T细胞介导的肿瘤控制中的作用。我们会从两个方面验证这一假说：1)明确天冬酰胺代谢调节的代谢途径(S)在抗肿瘤中的作用。肿瘤CD8+T细胞和2)天冬酰胺代谢在调节CD8+T细胞衰竭中的作用活体在PD-1阻断期间。在目标1中，我们将系统地确定代谢机制(S)，通过天冬酰胺通过比较野生型和CRISPR/Cas9编辑的ASNS-/-抗肿瘤CD8+T来调节CD8+T细胞细胞。天冬酰胺在不同代谢途径、蛋白质合成和细胞溶解中的命运(S)和贡献(S) 在一项新的研究中，将使用天冬酰胺、天冬氨酸和谷氨酰胺的同位素标记形式来评估T细胞的活性 T细胞与肿瘤细胞共培养体系。目标2将全面询问天冬酰胺的作用代谢，包括天冬酰胺的合成和吸收，利用功能基因组的扰动在耗竭的CD8+T细胞中靶向天冬酰胺合成酶和天冬酰胺转运蛋白SLC15A的方法在荷瘤小鼠的抗PD-1治疗中。天冬酰胺是一种组合方法补充或药物耗尽将揭示该途径的调节如何调节抗肿瘤T 细胞功能和与ICB的协同作用。我们的研究在概念上是新颖的，将解决我们对新陈代谢的理解中的一个重要差距抗肿瘤耗竭CD8+T细胞维持和功能反应的关键回路 PD-1治疗。由于人们对营养物质中T细胞代谢途径的使用和脆弱性知之甚少有限的肿瘤微环境，天冬酰胺代谢作为一种调节抗PD-1疗效的中枢代谢节点可能最终使新的临床策略得以改进 ICB疗法通过为T细胞提供代谢支持的临床反应。