Modulation of asparagine bioavailability and stress response signaling to enhance T cell robustness and maximize immunotherapy

调节天冬酰胺生物利用度和应激反应信号传导以增强 T 细胞稳健性并最大化免疫治疗

• 批准号: 10550241
• 负责人: Ruoning Wang
• 金额: $ 47.02万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10550241
• 关键词: Adoptive Cell Transfers; Amino Acids; Anabolism; Antitumor Response; Asparagine; Aspartate-Ammonia Ligase; Automobile Driving; B-Cell Leukemia; Binding; Biochemical Reaction; Biological Availability; CAR T cell therapy; Cancer Patient; Carbon; Cell Proliferation; Cell physiology; Cellular Metabolic Process; Clinical; Dependence; Energy Supply; Engineering; Generations; Genetic; Glucose; Glutamine; Growth; Immunologic Surveillance; Immunooncology; Immunotherapeutic agent; Immunotherapy; In Vitro; Intervention; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Metabolic; Metabolic Pathway; Metabolism; Molecular; Nitrogen; Non-Small-Cell Lung Carcinoma; Nutrient; Outcome; Outcome Assessment; Pathway interactions; Pre-Clinical Model; Process; Proliferating; Radioactive Tracers; Refractory; Regimen; Resources; Role; Signal Pathway; Signal Transduction; Source; Specificity; Stress; Stress Response Signaling; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tumor Immunity; anti-tumor immune response; biological adaptation to stress; c-myc Genes; cancer cell; cancer immunotherapy; cell growth; cytotoxic; dietary approach; effector T cell; extracellular; genetic approach; immune checkpoint blockade; immunoregulation; improved; in vivo; melanoma; metabolic fitness; metabolomics; neoplastic cell; novel; novel strategies; patient response; pharmacologic; programs; response; stable isotope; success; transcription factor; transcriptomics; treatment response; tumor; tumor initiation; tumor microenvironment; uptake

Summary: The exquisite specificity, amplitude, and quality of T cells govern tumor initiation, progression, and responses to therapy. Two of the most revolutionary and promising immunotherapies are the immune checkpoint blockade and the adoptive cell transfer, which are both dependent on the robust engagement of cytotoxic T effector (Teff) cells to control or eradicate cancer. A robust T cell-mediated anti-tumor response requires the coordination of nutrient and energy supplies with Teff cell expansion and function. However, the high metabolic demands of tumor cells compromise the function of Teff cells by competing for nutrients within the tumor micro-environment (TME). We propose that the critical barrier, which limits the patient’s response to immunotherapy, is the hostile metabolic microenvironment within tumors. We have previously shown that the transcription factors c-Myc and HIF1alpha are differentially required for driving the central carbon metabolic programs during T cell acti-vation and differentiation. We recently revealed that asparagine (Asn) is the most upregulated amino acid upon T cell activation, and its bioavailability represents a key metabolic node that governs the central carbon metab-olism and effector function in Teff cells. Some cancer cells solely rely on extracellular Asn to support growth and proliferation, representing a metabolic vulnerability of cancer. However, Teff cells can maintain an intracellular Asn pool for cell growth and function either through the uptake of extracellular Asn or through de novo biosyn-thesis of Asn, indicating a layer of metabolic plasticity of T cells. Enforced restriction of extracellular Asn rewires central carbon catabolic programs, leading to enhanced anti-tumor effector function in Teff cells. Moreover, these Teff cells are characterized by an enhanced ATF4 and Nrf2 signaling response. Hence, we hypothesize that modulation of Asn bioavailability can optimize carbon assimilation and integrate stress-response sig-naling pathways, enabling a robust anti-tumor response in metabolically restricted tumor microenviron-ments. To test our hypothesis, we propose to 1) decipher the reprogramming of central carbon metabolic path-ways and assess the impact of key metabolic steps on Teff cells in the context of Asn restriction; 2) determine the role of ATF4/Nrf2 axis in regulating the effector function of Teff cells; 3) target critical signaling and metabolic nodes to engineer central carbon catabolic programs, thus enhancing function and persistence of Teff cells, and 4) develop and test strategies to simultaneously exploit Asn dependence as a cancer cell metabolic vulnerability and maximize systemic anti-tumor immunity. Collectively, the completion of this project will reveal fundamental principles of the emerging connections between the tumor’s microenvironment, cell metabolism, and anti-tumor immunity. These studies are critical to developing novel approaches that improve clinical outcomes of cancer immunotherapy substantially.

摘要：T 细胞的精确特异性、幅度和质量控制着肿瘤的发生、进展和对治疗的反应，两种最具革命性和前景的免疫疗法是免疫检查点阻断和过继性细胞转移，这两种疗法都依赖于强大的免疫疗法。然而，细胞毒性 T 效应 (Teff) 细胞控制或根除癌症的强大 T 细胞介导的抗肿瘤反应需要协调营养和能量供应与 Teff 细胞的扩张和功能，从而损害肿瘤细胞的高代谢需求。的函数Teff 细胞通过竞争肿瘤微环境 (TME) 内的营养物质，我们提出限制患者对免疫治疗反应的关键障碍是肿瘤内的不利代谢微环境。我们最近发现天冬酰胺 (Asn) 是 T 细胞激活时上调最多的氨基酸，其生物利​​用度代表了关键的代谢。 Teff 细胞中控制中心碳代谢和效应器功能的节点。一些癌细胞仅依赖细胞外 Asn 来支持生长和增殖，这代表了癌症的代谢脆弱性。然而，Teff 细胞可以维持细胞内 Asn 库以促进细胞生长。并通过摄取细胞外 Asn 或通过 Asn 从头生物合成来发挥作用，这表明 T 细胞的代谢可塑性层被强制限制，从而重新连接了中心碳分解代谢程序。此外，这些 Teff 细胞的特点是 ATF4 和 Nrf2 信号反应增强，因此，我们发现调节 Asn 生物利用度可以优化碳同化并整合应激反应信号通路。在代谢受限的肿瘤微环境中实现强大的抗肿瘤反应为了检验我们的假设，我们建议1）破译中心碳代谢途径的重编程。并评估 Asn 限制下关键代谢步骤对 Teff 细胞的影响；2) 确定 ATF4/Nrf2 轴在调节 Teff 细胞效应功能中的作用；3) 靶向关键信号传导和代谢节点以设计中心碳分解代谢。计划，从而增强 Teff 细胞的功能和持久性，4) 开发和测试同时利用 Asn 依赖性作为癌细胞代谢脆弱性并最大化全身抗肿瘤免疫的策略。总的来说，该项目的完成将揭示 Teff 细胞的基本原理。肿瘤微环境、细胞代谢和抗肿瘤免疫之间的新兴联系对于开发显着改善癌症免疫治疗临床结果的新方法至关重要。