Investigating altered T-cell metabolism during chronic antigen encounter

研究慢性抗原遭遇过程中 T 细胞代谢的改变

• 批准号: 9975989
• 负责人: SANTOSHA VARDHANA
• 金额: $ 26.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9975989
• 关键词: Acetylcysteine; Affect; Amino Acids; Antigens; Antioxidants; Bioenergetics; Biological Markers; Biological Models; Biological Response Modifiers; Biopsy; Blocking Antibodies; Cell Survival; Cell physiology; Cells; Cellular Metabolic Process; Characteristics; Chronic; Citric Acid Cycle; Clinical; Cysteine; DNA; Data; Defect; Environment; Epigenetic Process; Exposure to; Face; Failure; Functional disorder; Funding; Gene Expression; Generations; Genetic; Glucose; Glutamine; Glutathione; Half-Life; Histones; Homeostasis; Immune; Immune Targeting; Immune response; Immunity; Immunology; Immunosuppression; Immunotherapy; Impairment; In Vitro; Infiltration; International; Investigation; Laboratories; Lymphoma; MAP2K1 gene; MEKs; Malignant Neoplasms; Measures; Medical Oncology; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolic dysfunction; Metabolism; Methyltransferase; Minority; Mus; Non-Essential Amino Acid; Nucleotide Biosynthesis; Nutrient; Oxidation-Reduction; Oxidative Stress; Oxides; Pathway interactions; Patients; Pharmacology; Physicians; Positioning Attribute; Proliferating; Reaction; Reactive Oxygen Species; Research; Research Personnel; Sampling; Scientist; Services; Signal Transduction; Stress; System; T cell response; T cell therapy; T-Cell Proliferation; T-Lymphocyte; Testing; Training; Tumor Antigens; Tumor Immunity; Waste Products; anti-PD1 therapy; anti-tumor immune response; cancer cell; cancer immunotherapy; cancer subtypes; cancer therapy; career; chromatin modification; chromatin remodeling; cytotoxic; demethylation; effector T cell; engineered T cells; exhaustion; experience; immune checkpoint; immune checkpoint blockade; immunoregulation; improved; in vivo; in vivo Model; mouse model; novel; novel strategies; nucleotide metabolism; patient response; programs; treatment response; tumor; tumor microenvironment; uptake

PROJECT SUMMARY/ABSTRACT Despite recent advances in the targeting of immune checkpoints across malignancies, many patients fail to respond to treatment, suggesting alternative mechanisms of immunosuppression. Metabolic dysfunction within tumor-infiltrating T-cells has emerged as a potential mechanism by which long-term anti-tumor immunity is impaired. The mechanism by which altered metabolism suppresses intratumoral T-cell function, however, remains to be fully characterized. Cellular metabolites not only supply the bioenergetics needs of proliferating immune cells, but also regulate gene expression by serving as the substrates for chromatin modifications. Preliminary data presented in this proposal utilize a combination of in vitro and in vivo systems to explore the metabolic liabilities of T-cells during chronic exposure to tumor antigens. Under these conditions, T-cells experience high levels of oxidative stress. This compromises the ability of T-cells to oxidize glucose and glutamine within the TCA cycle, leading to bioenergetic compromise that impairs nucleotide biosynthesis and alters the availability of substrates for DNA and histone demethylation reactions. Enhancing redox homeostasis has beneficial effects on anti-tumor T-cell immunity in vitro as well as in vivo. Thus, the efficacy of T-cells within the tumor microenvironment may be primarily limited by metabolic alterations that generate redox stress. This hypothesis will be rigorously tested by (1) using a combination of in vitro and in vivo models of T-cell exhaustion in both mice and primary patient tumors to define the impact of chronic antigen-driven metabolic alterations on T-cell proliferation, chromatin modifications, and effector function, (2) determining how cysteine limitation exacerbates T-cell dysfunction within the tumor microenvironment, and (3) determining whether enhancing redox homeostasis, either by increasing intracellular cysteine availability or limiting the generation of oxidative stress can reverse metabolic T-cell dysfunction and enhance anti-tumor immunity. The proposed investigations will expand the armamentarium of strategies to enhance immune responses in cancer, particularly for the patients who are unresponsive to anti-PD-1 therapy. The applicant, Dr. Santosha Vardhana, an Assistant Attending with the Lymphoma Service at Memorial Sloan Kettering Cancer Center, has outlined a 5-year career plan that builds on his scientific background in immunology and cellular metabolism as well as his clinical training in medical oncology and immunotherapy. Dr. Vardhana will conduct the proposed research under the mentorship of Dr. Craig Thompson, an internationally recognized expert in immunology and metabolism with a strong track record of training successful physician scientists, with co-mentorship by Dr. Jedd Wolchok, a highly recognized expert in cancer immunotherapy with significant experience interrogating T- cell function in both mouse models and primary patient samples. MSKCC provides the ideal institutional environment for Dr. Vardhana to embark on the proposed research program and transition to a position as an independent academic investigator with his own laboratory and R01 funding.

项目总结/摘要 尽管最近在靶向恶性肿瘤免疫检查点方面取得了进展，但许多患者未能在免疫检查点方面取得进展。 对治疗有反应，提示免疫抑制的替代机制。体内代谢功能障碍 肿瘤浸润性T细胞已经成为一种潜在的机制，通过这种机制， 受损。然而，代谢改变抑制肿瘤内T细胞功能的机制， 仍有待充分定性。细胞代谢物不仅提供增殖所需的生物能量， 免疫细胞，而且还通过作为染色质修饰的底物来调节基因表达。 本提案中提出的初步数据利用体外和体内系统的组合来探索 T细胞在长期暴露于肿瘤抗原期间的代谢负债。在这种情况下，T细胞 经历高水平的氧化应激。这损害了T细胞氧化葡萄糖的能力， TCA循环中的谷氨酰胺，导致生物能量损害，损害核苷酸生物合成， 改变了DNA和组蛋白去甲基化反应底物的可用性。增强氧化还原 体内平衡对体外以及体内抗肿瘤T细胞免疫具有有益作用。因此， 肿瘤微环境中T细胞的数量可能主要受到代谢改变的限制， 氧化还原应激这一假设将通过（1）使用体外和体内模型的组合进行严格检验 小鼠和原发性患者肿瘤中T细胞耗竭的影响，以确定慢性抗原驱动的 代谢改变对T细胞增殖，染色质修饰和效应功能，（2）确定如何 半胱氨酸限制加剧肿瘤微环境内的T细胞功能障碍，和（3）确定 无论是通过增加细胞内半胱氨酸的可用性还是通过限制细胞内半胱氨酸的含量来增强氧化还原稳态， 氧化应激的产生可以逆转代谢性T细胞功能障碍并增强抗肿瘤免疫。的 拟议的研究将扩大策略的工具箱以增强癌症中的免疫应答， 特别是对于对抗PD-1治疗无反应的患者。申请人Santosha Vardhana博士 纪念斯隆凯特琳癌症中心淋巴瘤服务的助理，概述了一个 5-一年的职业生涯计划，建立在他在免疫学和细胞代谢的科学背景，以及 他在医学肿瘤学和免疫疗法方面的临床训练。Vardhana博士将进行拟议的研究 在国际公认的免疫学专家克雷格·汤普森博士的指导下， 代谢与培训成功的医生科学家的良好记录，与共同导师博士。 Jedd Wolchok是一位高度认可的癌症免疫治疗专家，具有丰富的询问T细胞的经验， 小鼠模型和原代患者样品中的细胞功能。MSKCC提供理想的机构 环境博士Vardhana走上拟议的研究计划，并过渡到作为一个职位， 拥有自己的实验室和R 01基金的独立学术研究者。