Exploiting a novel regulator of immunometabolism to enhance immunotherapy

利用新型免疫代谢调节剂来增强免疫治疗

• 批准号: 10517766
• 负责人: Edward J Usherwood
• 金额: $ 49.35万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517766
• 关键词: Adenocarcinoma Cell; Adoptive Immunotherapy; Adoptive Transfer; Affect; Antigens; Area; CD8-Positive T-Lymphocytes; CD8B1 gene; Carbon; Cell Survival; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cellular Metabolic Process; Data; Disease remission; Dominant-Negative Mutation; Energy-Generating Resources; Engineering; Ensure; Environment; Excision; Exposure to; Future; Gene Expression Profiling; Gene Silencing; Genes; Genetic Transcription; Glucose; Glutamine; Glycolysis; Granzyme; Human; Immunity; Immunotherapy; Knowledge; Liquid substance; MC38; Malignant Neoplasms; Measures; Mediating; Melanoma Cell; Memory; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Mus; Patients; Phenocopy; Phenotype; Reagent; Reporter; Research; Resistance development; Respiration; Role; Solid Neoplasm; Source; Stable Isotope Labeling; Surface; System; T cell differentiation; T cell response; T cell therapy; T-Cell Receptor; T-Lymphocyte; Tamoxifen; Testing; Transcription Repressor; Translating; Tumor Antigens; Tumor Immunity; Up-Regulation; anti-cancer; anti-tumor immune response; base; cancer therapy; cell motility; cell type; chimeric antigen receptor T cells; chromatin remodeling; combat; engineered T cells; exhaustion; experimental study; flexibility; genetic corepressor; improved; interest; knock-down; melanoma; mitochondrial metabolism; mutant; neoplastic cell; novel; patient population; recruit; response; success; transcription factor; transcription factor UBF; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

Adoptive T cell therapy for cancer has proven remarkably successful and is capable of producing high response rates and dramatic remission in some patients. Currently it is more effective against liquid than solid tumors, due to the environment within tumors being hostile for T cell survival and function. As is true of many tumors, melanomas are highly glycolytic, and deplete the local glucose concentration. Melanomas that develop resistance to Vemurafenib undergo metabolic remodeling to become dependent upon glutamine. As both glucose and glutamine are essential for effector CD8 T cell differentiation and anti-tumor effector functions, the T cell response is compromised in the tumor microenvironment. Advances in adoptive T cell therapy have focused mostly on better targeting and activation of tumor-specific T cells, however they may still fail to thrive in this metabolically challenging environment. Engineering cells with the flexibility to use multiple carbon sources, with less reliance on glucose and glutamine, is one very promising approach that could be layered onto any tumor targeting strategy. In this application we show that CD8 T cells lacking in the transcriptional repressor Zbtb20 display enhanced glycolytic and mitochondrial metabolism, and increased fuel flexibility relative to wild- type cells. Single cell transcriptional profiling confirmed these metabolic changes and confirmed phenotypic studies showing a skewing toward the memory fate. Consistent with these attributes being favorable for anti- tumor immunity, we found adoptive transfer of Zbtb20-deficient CD8 T cells conferred superior immunity upon challenge with melanoma or adenocarcinoma cells. Therefore, suppression of Zbtb20 is a very promising approach to improve T cell metabolism for adoptive immunotherapy. In this proposal we determine the precise molecular mechanisms underlying enhanced anti-tumor immunity, mechanisms for elevated glycolytic and mitochondrial metabolism, and the extent to which each change is responsible for anti-tumor immunity. We also determine the extent to which a dominant negative mutant of Zbtb20 can replicate enhanced protection observed in Zbtb20 deficient cells, as this is more readily translatable to human T cells. These studies will reveal the mechanism(s) by which Zbtb20 deficiency enhances anti-tumor immunity and investigates strategies that can be translated into human T cell adoptive therapy.

癌症的过继T细胞疗法已被证明非常成功，并能够产生高反应性 一些患者的缓解率和显着缓解。目前，它对液体肿瘤比固体肿瘤更有效， 由于肿瘤内的环境不利于T细胞的生存和功能。就像许多肿瘤一样， 黑色素瘤是高度糖酵解的，会消耗局部的葡萄糖浓度。发生的黑色素瘤 对维莫拉非尼的耐药性经历代谢重塑，变得依赖谷氨酰胺。因为两者都是 葡萄糖和谷氨酰胺是CD8效应T细胞分化和抗肿瘤效应功能所必需的， T细胞反应在肿瘤微环境中受到损害。过继T细胞治疗的进展 主要集中在更好的靶向和激活肿瘤特异性T细胞，然而它们可能仍然无法在 这种具有新陈代谢挑战性的环境。灵活使用多种碳源的工程电池， 减少对葡萄糖和谷氨酰胺的依赖，是一种非常有希望的方法，可以在任何 肿瘤靶向策略。在这个应用中，我们发现CD8 T细胞缺乏转录抑制因子 与野生动物相比，Zbtb20表现出增强的糖酵解和线粒体代谢，以及更高的燃料灵活性 键入单元格。单细胞转录图谱证实了这些代谢变化，并确认了表型 研究表明，记忆的命运正在发生倾斜。与这些属性一致的有利于反 肿瘤免疫，我们发现过继转移Zbtb20缺陷的CD8T细胞可以获得更好的免疫力 挑战黑色素瘤或腺癌细胞。因此，抑制Zbtb20是一个很有前途的 改善T细胞代谢用于过继免疫治疗的途径。在这份提案中，我们确定了准确的 增强抗肿瘤免疫的分子机制，糖酵解升高和 线粒体代谢，以及每个变化对抗肿瘤免疫的影响程度。我们也 确定Zbtb20的显性负性突变体可以复制观察到的增强保护的程度 在Zbtb20缺陷细胞中，因为这更容易被翻译成人类T细胞。这些研究将揭示 Zbtb20缺陷增强抗肿瘤免疫的机制及策略研究(S) 被转化为人类T细胞过继治疗。