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: 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
• 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

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.

针对癌症的连续性T细胞疗法已被证明非常成功，并且能够产生高应答。 在某些患者中，治疗效果显著。目前，它对液体肿瘤比实体肿瘤更有效， 因为肿瘤内的环境不利于T细胞的存活和功能。与许多肿瘤一样， 黑色素瘤是高度糖酵解的，并耗尽局部的葡萄糖浓度。黑色素瘤的发展 对维罗非尼的抗性经历代谢重塑以变得依赖于谷氨酰胺。既是 葡萄糖和谷氨酰胺是效应CD 8 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。过继性T细胞治疗的进展 主要集中在更好地靶向和激活肿瘤特异性T细胞，但它们仍然可能无法在肿瘤中茁壮成长。 这种代谢挑战性的环境工程细胞具有使用多种碳源的灵活性， 减少对葡萄糖和谷氨酰胺的依赖，是一种非常有前途的方法，可以分层到任何 肿瘤靶向策略。在本申请中，我们表明，缺乏转录抑制因子的CD 8 T细胞， Zbtb 20显示出增强的糖酵解和线粒体代谢，以及相对于野生型Zbtb 20增加的燃料灵活性。 类型细胞。单细胞转录谱证实了这些代谢变化，并证实了表型 研究显示记忆的命运会有偏差。与这些属性相一致，有利于抗- 在肿瘤免疫中，我们发现Zbtb 20缺陷型CD 8 T细胞的过继转移赋予了肿瘤细胞上级免疫。 用黑色素瘤或腺癌细胞攻击。因此，抑制Zbtb 20是一种非常有前途的方法。 改善过继免疫治疗的T细胞代谢的方法。在本提案中，我们确定了 增强抗肿瘤免疫的分子机制，糖酵解和 线粒体代谢，以及每种变化在多大程度上负责抗肿瘤免疫。我们也 确定Zbtb 20的显性失活突变体可以复制观察到的增强的保护的程度 在Zbtb 20缺陷细胞中，因为这更容易翻译为人T细胞。这些研究将揭示 Zbtb 20缺陷增强抗肿瘤免疫的机制，并研究可以 转化为人类T细胞过继疗法。