Naïve T cell archetypes and anti-tumor immunity

幼稚 T 细胞原型和抗肿瘤免疫

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 T 细胞免疫疗法彻底改变了癌症治疗，强调了这些细胞控制癌症的能力尽管如此，迄今为止，T 细胞免疫疗法仅利用了效应 T 细胞。我们和其他人最近发现，细胞是 T 细胞介导的免疫的原始基质。 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值得注意的是，幼稚 T 细胞的异质性不是固定的，而是对遗传或环境信号相当敏感。由突变或病原体经历引起的簇组成的变化可能会产生显着的变化，并且在某些情况下在某些情况下，幼稚 T 细胞对同源抗原的反应能力产生截然相反的影响。提出了幼稚 T 细胞是微生物经验宝库的创新概念。它们未来在同源抗原相遇期间的激活潜力，包括在抗肿瘤免疫反应期间。我们建议：（1）测试病原体暴露对初始 CD4+ 和 CD8+ T 细胞和 (2) 将这些幼稚 T 细胞固有的与抗原无关的转录变化关联起来我们的方法将包括测试一系列微生物经验。（即：细菌、病毒和蠕虫感染）以全面分析不同类型感染的影响。建立初始 T 细胞的经验模制转录状态与其能力之间的关系为了发起抗肿瘤免疫反应，我们将在植入的和我们的建议有可能改变我们对自体肿瘤模型的理解。环境在初始 T 细胞水平上塑造免疫状态以及随之而来的对免疫的影响，包括抗肿瘤免疫。