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.

项目摘要/摘要 T细胞免疫疗法彻底改变了癌症治疗，突显了这些细胞控制的能力肿瘤生长。尽管如此，迄今为止，T细胞免疫疗法仅探索了效应T细胞。天真细胞是T细胞介导的免疫力的原始底物。我们和其他人最近发现这很幼稚 T细胞以不同的转录异质状态存在，包括显示静态表型的簇或表达I型干扰素反应基因或IL-4反应基因或TCR途径基因或记忆样基因。幼稚的T细胞异质性不是固定的，而是对遗传或环境信号敏感的。尤其，突变或病原体经验引起的簇组合物的变化可能具有显着，在某些情况下病例，幼稚T细胞对同源抗原反应的能力截然相反。我们放在这里将幼稚的T细胞是微生物体验的存储库来转发创新的概念。反过来，建立它们在同源抗原相遇期间的未来激活潜力，包括抗肿瘤免疫反应期间。我们建议：（1）测试病原体暴露对幼稚CD4+转录异质性和 CD8+ T细胞和（2）将这些抗原 - 敏锐的转录变化与幼稚T细胞的内在变化相关对抗肿瘤免疫反应的影响。我们的方法将包括测试一系列微生物体验（即：细菌，病毒和蠕虫感染）全面介绍了不同类型的感染的影响。确定幼稚T细胞的经验 - 磨性转录状态与其能力之间的关系为了安装抗肿瘤的免疫反应，我们将测试病原体条件的幼稚T细胞，并在植入和作者肿瘤模型。我们的建议有可能改变我们对环境在幼稚的T细胞水平上塑造免疫抑制素，从而对免疫产生影响，包括抗肿瘤免疫。