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: 10380065
• 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/10380065
• 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; 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.

项目概要/摘要 尽管最近在针对恶性肿瘤的免疫检查点方面取得了进展，但许多患者未能 对治疗有反应，表明免疫抑制的替代机制。体内代谢功能障碍 肿瘤浸润 T 细胞已成为长期抗肿瘤免疫的潜在机制。 受损。然而，代谢改变抑制瘤内 T 细胞功能的机制 仍有待充分表征。细胞代谢物不仅满足增殖的生物能需求 免疫细胞，还通过作为染色质修饰的底物来调节基因表达。 该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担。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循环中的谷氨酰胺，导致生物能损害，损害核苷酸生物合成和 改变 DNA 和组蛋白去甲基化反应底物的可用性。增强氧化还原 体内稳态对体外和体内的抗肿瘤 T 细胞免疫都有有益的影响。由此可见，功效 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，这些改变产生 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检验 小鼠和原发性患者肿瘤中 T 细胞耗竭的结果，以确定慢性抗原驱动的影响 T 细胞增殖、染色质修饰和效应器功能的代谢改变，(2) 确定如何 半胱氨酸限制加剧了肿瘤微环境中的 T 细胞功能障碍，并且 (3) 确定 是否通过增加细胞内半胱氨酸的可用性或限制 氧化应激的产生可以逆转代谢性T细胞功能障碍，增强抗肿瘤免疫力。这 拟议的研究将扩大增强癌症免疫反应的策略武器库， 特别是对于抗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中心的一位助理概述了 五年职业计划建立在他在免疫学和细胞代谢方面的科学背景以及 他接受过肿瘤内科和免疫治疗方面的临床培训。 Vardhana 博士将进行拟议的研究 在国际公认的免疫学专家 Craig Thompson 博士的指导下 代谢在培训成功的医师科学家方面有着良好的记录，并由 Dr. 共同指导。 Jedd Wolchok 是一位备受认可的癌症免疫治疗专家，在询问 T- 小鼠模型和主要患者样本中的细胞功能。 MSKCC 提供理想的机构 为 Vardhana 博士着手拟议的研究计划并过渡到担任 独立学术研究者，拥有自己的实验室和 R01 资助。