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

基本信息

批准号：
10654844
负责人：
Edward J Usherwood
金额：
$ 48.37万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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/10654844
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 Cytoprotection Data Disease remission Dominant-Negative Mutation Energy-Generating Resources Engineering Ensure Environment Excision Exposure to Future Gene Expression Profiling Gene Expression Regulation 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 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 migration mitochondrial metabolism mutant neoplastic cell novel patient population recruit response restraint success transcription factor transcription factor UBF transcriptome sequencing tumor tumor growth tumor microenvironment

项目摘要

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.

事实证明，用于癌症的收养T细胞疗法已取得了非常成功的成功，并且能够产生高反应某些患者的比率和急剧缓解。目前，它比实体瘤更有效，由于肿瘤中的环境是敌对的，用于T细胞的存活和功能。就像许多肿瘤一样黑色素瘤是高度糖酵解的，并耗尽了局部葡萄糖浓度。发育的黑色素瘤对维美富尼的抗性会经历代谢重塑，以依赖谷氨酰胺。两者兼而有之葡萄糖和谷氨酰胺对于效应子CD8 T细胞分化和抗肿瘤效应函数至关重要， T细胞反应在肿瘤微环境中受到损害。收养T细胞疗法的进步已有主要专注于更好地靶向和激活肿瘤特异性T细胞，但是它们可能仍未在这个代谢充满挑战的环境。具有使用多个碳源的灵活性的工程单元对葡萄糖和谷氨酰胺的依赖较少，是一种非常有前途的方法，可以分层到任何肿瘤靶向策略。在此应用中，我们表明转录阻遏物缺乏CD8 T细胞 ZBTB20显示增强的糖酵解和线粒体代谢，并提高了相对于野生的燃料灵活性类型单元格。单细胞转录分析证实了这些代谢变化并确认了表型研究表明偏向记忆命运。与这些属性一致肿瘤免疫力，我们发现ZBTB20缺陷型CD8 T细胞的产卵转移在挑战黑色素瘤或腺癌细胞。因此，抑制ZBTB20是一个非常有前途的改善T细胞代谢的方法以进行继发性免疫疗法。在此提案中，我们确定了确切的抗肿瘤免疫力增强的分子机制，糖酵解和升高的机制线粒体代谢，以及每个变化在多大程度上负责抗肿瘤免疫力。我们也是确定ZBTB20的主要负突变体可以在多大程度上复制观察到的增强保护在ZBTB20缺陷细胞中，因为这更容易翻译成人类T细胞。这些研究将揭示 ZBTB20缺乏增强抗肿瘤免疫的机制，并研究可以被翻译成人类T细胞产物疗法。