Naïve T cell archetypes and anti-tumor immunity

幼稚 T 细胞原型和抗肿瘤免疫

• 批准号: 10741153
• 负责人: Sourav Ghosh
• 金额: $ 25.13万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10741153
• 关键词: Ablation; Admixture; Antigens; Automobile Driving; Bacteria; Bacterial Infections; CD8-Positive T-Lymphocytes; CD8B1 gene; Calibration; Cancer Model; Cataloging; Cell Differentiation process; Cells; Cellular Immunity; Citrobacter rodentium; Complex; Contracts; Elements; Environment; Equilibrium; Frequencies; Future; Gene Expression; Genes; Genetic; Genetic Transcription; Growth; Helminths; Heterogeneity; Host Defense; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunity; Immunoglobulin Domain; Immunotherapy; Implant; Induced Mutation; Infection; Innate Immune Response; Interferon Type I; Interleukin-4; Lymphocytic choriomeningitis virus; Malignant neoplasm of liver; Memory; Modeling; Molds; Mus; Nature; Nippostrongylus; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Population; Proliferating; Regulatory T-Lymphocyte; Role; Self-Injurious Behavior; Shapes; Signal Transduction; Simian virus 40; Source; Suppressor-Effector T-Lymphocytes; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Testing; Transgenic Organisms; Translating; Transplantation; Tumor Antigens; Tumor Immunity; Virus; Virus Diseases; adaptive immune response; adaptive immunity; anti-PD-1; anti-tumor immune response; cancer cell; cancer infiltrating T cells; cancer therapy; cell killing; effector T cell; exhaustion; experience; genetic risk factor; germ free condition; helminth infection; immune checkpoint; immunoregulation; improved; innovation; melanoma; microbial; mouse model; novel; pathogen; pathogen exposure; prevent; repository; response; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT T cell immunotherapy have revolutionized cancer treatment, underscoring the ability of these cells in controlling tumor growth. Notwithstanding, T cell immunotherapy, heretofore, has only exploited effector T cells. Naïve T cells are the primordial substrate of T cell-mediated immunity. We and others have recently discovered that naïve T cells exist in distinct transcriptionally heterogenous states including clusters displaying a quiescent phenotype or expressing type I interferon response genes or IL-4 response genes or TCR pathway genes or memory-like genes. Naïve T cell heterogeneity is not fixed, but rather sensitive to genetic or environmental signals. Notably, changes in cluster composition induced by mutations or pathogen experience can have significant and, in some cases, diametrically opposite effects in the ability of naïve T cells to respond to cognate antigen. Here we put forward the innovative concept that naïve T cells are a repository of microbial experience. This in turn, establishes their future activation potential during cognate antigen encounter, including during anti-tumor immune response. We propose to: (1) test the effect of pathogen exposure on the transcriptional heterogeneity of naïve CD4+ and CD8+ T cells and (2) correlate these antigen-agnostic transcriptional changes intrinsic to naïve T cells for their effect on anti-tumor immune responses. Our approach will include testing a spectrum of microbial experiences (i.e.: bacterial, viral, and helminth infection) to comprehensively profile the effect of different types of infections. To establish the relationship between experience-moulded transcriptional states of naïve T cells and their ability to mount an anti-tumor immune response, we will test pathogen-conditioned naïve T cells in implanted and authoctonous tumor models. Our proposal has the potential to transform our understanding on how the environment shapes the immune state at the level of naïve T cells and the consequent impact on immunity, including anti-tumor immunity.

项目总结/摘要 T细胞免疫疗法已经彻底改变了癌症治疗，强调了这些细胞在控制癌症方面的能力。 肿瘤生长尽管如此，迄今为止，T细胞免疫疗法仅利用效应T细胞。天真的T 细胞是T细胞介导的免疫的原始底物。我们和其他人最近发现， T细胞以不同的转录异质状态存在，包括显示静止表型的簇 或表达I型干扰素应答基因或IL-4应答基因或TCR途径基因或记忆样 基因.幼稚T细胞的异质性不是固定的，而是对遗传或环境信号敏感。值得注意的是， 由突变或病原体经历引起的簇组成的变化可以具有显著的，并且在一些情况下， 在一些情况下，幼稚T细胞对同源抗原的反应能力完全相反。在这里我们把 提出了创新的概念，即幼稚T细胞是微生物经验的储存库。这反过来又确立了 它们在同源抗原遭遇期间，包括在抗肿瘤免疫应答期间的未来活化潜力。 我们建议：（1）测试病原体暴露对幼稚CD 4+转录异质性的影响， CD 8 + T细胞和（2）将这些抗原不可知的转录变化与幼稚T细胞固有的抗原不可知的转录变化相关联， 对抗肿瘤免疫应答的影响。我们的方法将包括测试一系列微生物的经验， (i.e.:细菌、病毒和蠕虫感染）以全面描述不同类型感染的影响。 建立经验塑造的幼稚T细胞转录状态与其能力之间的关系 为了建立抗肿瘤免疫反应，我们将在植入的和 自发性肿瘤模型。我们的建议有可能改变我们对如何 环境在初始T细胞水平上塑造免疫状态，并对免疫产生影响， 包括抗肿瘤免疫。