Negative feedback control of T cells in tolerance and cancer - from pathways to biomarkers

T 细胞在耐受性和癌症中的负反馈控制 - 从途径到生物标志物

• 批准号: MR/V009052/1
• 负责人: David Bending
• 金额: $ 177.66万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV009052%2F1
• 关键词: Negative; feedback; control; cells; tolerance

T cells are vital immune cells that help fight infections and cancer. T cells must strike a balance between successfully clearing harmful invaders and the collateral damage they might inflict in achieving this (called immunopathology). The T cell system therefore has many brakes which it can apply to control the level of immune response. I have developed new tools that can follow T cell responses and identify when and how they switch on these immune brakes. I believe that these brakes that have developed to prevent autoimmunity account for why T cells are prevented from killing cancer cells. This study will initially utilise normal healthy settings to understand how three key brakes, PD1, Lag3 (also called immune 'checkpoints') and IL-10 control T cell responses. My early data suggest that drugs that block the functions of some of these molecules can induce unique features within T cells, called 'biomarkers', which could be used to monitor whether an individual is responding to therapy. I will therefore apply the knowledge gained from studying how these brakes control T cell responses in normal settings to several cancer models in mice. The aim will be to identify biomarkers for successful responders to immune checkpoint blockade in cancer. I envisage that this work will lead to a better understanding of these immune 'checkpoints' in both normal and cancer settings. In addition, the study will identify potential 'biomarkers' that could be used in the future to predict patient responses to particular immunotherapies.

T细胞是帮助对抗感染和癌症的重要免疫细胞。T细胞必须在成功清除有害入侵者和它们在实现这一目标时可能造成的附带损害（称为免疫病理学）之间取得平衡。因此，T细胞系统有许多制动器，可以用来控制免疫反应的水平。我已经开发了新的工具，可以跟踪T细胞反应，并确定它们何时以及如何打开这些免疫刹车。我相信这些为防止自身免疫而开发的刹车解释了为什么T细胞被阻止杀死癌细胞。这项研究最初将利用正常的健康环境来了解三个关键制动器，PD 1，Lag 3（也称为免疫“检查点”）和IL-10如何控制T细胞反应。我的早期数据表明，阻断其中一些分子功能的药物可以诱导T细胞内的独特功能，称为“生物标志物”，可用于监测个体是否对治疗有反应。因此，我将把从研究这些制动器如何在正常情况下控制T细胞反应中获得的知识应用于小鼠的几种癌症模型。目的是确定癌症免疫检查点阻断成功应答者的生物标志物。我设想，这项工作将导致更好地了解这些免疫“检查点”在正常和癌症的设置。此外，该研究将确定潜在的“生物标志物”，可用于未来预测患者对特定免疫疗法的反应。

项目成果

T-cell response to checkpoint blockade immunotherapies: from fundamental mechanisms to treatment signatures.

• DOI: 10.1042/ebc20220247
• 发表时间: 2023-09-28
• 期刊: Essays in biochemistry
• 影响因子: 6.4

Antigen and Checkpoint Receptor Recalibration of T Cell Receptor Signal Strength

T 细胞受体信号强度的抗原和检查点受体重新校准

• DOI: 10.1101/2021.03.02.431957
• 发表时间: 2021
• 作者: Elliot T

Nur77-Tempo mice reveal T cell steady state antigen recognition.

• DOI: 10.1093/discim/kyac009
• 发表时间: 2022-12-22
• 期刊: Discovery immunology
• 作者: Elliot TAE;Jennings EK;Lecky DAJ;Rouvray S;Mackie GM;Scarfe L;Sheriff L;Ono M;Maslowski KM;Bending D
• 通讯作者: Bending D

Long-term antibiotic exposure promotes mortality after systemic fungal infection by driving lymphocyte dysfunction and systemic escape of commensal bacteria.

• DOI: 10.1016/j.chom.2022.04.013
• 发表时间: 2022-07-13
• 期刊: CELL HOST & MICROBE
• 影响因子: 30.3
• 作者: Drummond, Rebecca A.;Desai, Jigar, V;Ricotta, Emily E.;Swamydas, Muthulekha;Deming, Clay;Conlan, Sean;Quinones, Mariam;Matei-Rascu, Veronika;Sherif, Lozan;Lecky, David;Lee, Chyi-Chia R.;Green, Nathaniel M.;Collins, Nicholas;Zelazny, Adrian M.;Prevots, D. Rebecca;Bending, David;Withers, David;Belkaid, Yasmine;Segre, Julia A.;Lionakis, Michail S.
• 通讯作者: Lionakis, Michail S.