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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细胞共抑制性检查点程序性细胞死亡1（PD-1）在维持T细胞增殖中起关键作用。外周免疫耐受然而，PD-1通路可以被慢性病原体和肿瘤细胞，以促进免疫逃避。使用阻断PD的抗体的免疫检查点阻断（ICB）- 1/PD-L1配体相互作用在癌症临床试验中取得了显著成功。尽管诱导在一个患者子集中的持久反应，大多数患者在治疗后没有发展稳定的缓解。因此，我们认为，关键是要了解与免疫反应和抵抗相关的免疫和细胞特征， ICB。代谢重构与免疫系统的发育、分化和激活有着内在的联系，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，包括在ICB治疗期间控制耗尽的抗肿瘤T细胞的再活力的代谢途径。我们的初步研究发现天冬酰胺合成酶（Asns）是一种新的抗肿瘤代谢调节因子。肿瘤CD 8 + T细胞对抗PD-1治疗的反应，并为天冬酰胺的中心作用提供了证据在调节抗PD-1治疗在CD 8 + T细胞介导的肿瘤控制中的功效中，抗PD-1代谢的作用是显著的。我们将在两个目标中检验这一假设：1）定义抗-HCV中天冬酰胺代谢调节的代谢途径。肿瘤CD 8 + T细胞和2）确定天冬酰胺代谢在调节CD 8 + T细胞耗竭中的作用- 在PD-1阻断期间体内。在目标1中，我们将系统地确定代谢机制，通过比较野生型和CRISPR/Cas9编辑的Asns-/-抗肿瘤CD 8 + T细胞，天冬酰胺调节CD 8 + T细胞细胞天冬酰胺对不同代谢途径、蛋白质合成和细胞溶解的命运和贡献 T细胞活性将使用同位素标记形式的天冬酰胺、天冬氨酸和谷氨酰胺在一种新的与T细胞和肿瘤细胞的共培养系统。目的2将全面探讨天冬酰胺的作用代谢，包括天冬酰胺合成和摄取，通过利用功能基因组扰动靶向耗尽的CD 8 + T细胞中的天冬酰胺合成酶和天冬酰胺转运蛋白SLC 15 A的方法在抗PD-1治疗期间，在荷瘤小鼠中。组合方法，其中天冬酰胺是补充或耗尽的抗肿瘤药物将揭示该途径的调节如何调节抗肿瘤T细胞。细胞功能并与ICB协同作用。我们的研究在概念上是新颖的，将解决我们对代谢的理解中的一个重要空白。在抗肿瘤过程中，对耗尽的抗肿瘤CD 8 + T细胞的维持和功能反应至关重要的电路。 PD-1治疗。由于人们对营养物质中代谢途径的使用和T细胞的脆弱性知之甚少，有限的肿瘤微环境，天冬酰胺代谢的鉴定和成功验证，调节抗PD-1疗效的中心代谢节点可能最终使新的临床策略能够改善通过为T细胞提供代谢支持来改善ICB治疗的临床反应。