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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要尽管最近在跨恶性肿瘤靶向免疫检查点方面取得了进步，但许多患者未能对治疗的反应，提示免疫抑制的替代机制。内部代谢功能障碍肿瘤浸润的T细胞已成为长期抗肿瘤免疫力的潜在机制受损。但是，改变新陈代谢抑制肿瘤内T细胞功能的机制，但是仍然有待充分的特征。细胞代谢产物不仅满足了增殖的生物能量需求免疫细胞，但也通过作为染色质修饰的底物来调节基因表达。本提案中提供的初步数据利用体外和体内系统的组合来探索长期暴露于肿瘤抗原期间，T细胞的代谢负债。在这些条件下，T细胞经历高水平的氧化应激。这损害了T细胞氧化葡萄糖和 TCA周期内的谷氨酰胺，导致生物能妥协损害核苷酸生物合成和改变了DNA和组蛋白脱甲基反应的底物的可用性。增强氧化还原稳态对体外和体内的抗肿瘤T细胞免疫具有有益的影响。因此，功效肿瘤微环境内的T细胞可能主要受到代谢改变的限制氧化还原应力。该假设将通过（1）使用体外和体内模型的组合进行严格测试小鼠和原发性肿瘤的T细胞疲惫，以定义慢性抗原驱动的影响 T细胞增殖，染色质修饰和效应子功能的代谢改变，（2）确定如何半胱氨酸的限制加剧了肿瘤微环境内的T细胞功能障碍，并且（3）确定是通过增加细胞内半胱氨酸的可用性还是限制氧化应激的产生会逆转代谢T细胞功能障碍并增强抗肿瘤免疫力。这拟议的调查将扩大策略的武器库，以增强癌症的免疫反应，特别是对于对抗PD-1治疗无反应的患者。申请人Santosha Vardhana博士，在纪念斯隆·克特林癌症中心参加淋巴瘤服务的助手，概述了 5年的职业计划基于他的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培训。 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（Craig Thompson）的指导下代谢具有培训成功的医师科学家的良好记录，并由博士博士的同事制度 Jedd Wolchok是癌症免疫疗法的备受认可的专家，具有巨大的经验，询问T- 小鼠模型和主要患者样品中的细胞功能。 MSKCC提供理想的机构 Vardhana博士启动拟议的研究计划并过渡到一个地位的环境独立的学术研究员与自己的实验室和R01资金。