Tumour metabolic and immune landscape in spatial resolution: using engineered bacterial cancer therapy to enhance anti-tumour T cell responses.

空间分辨率下的肿瘤代谢和免疫景观：使用工程细菌癌症疗法增强抗肿瘤 T 细胞反应。

• 批准号: 2738818
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2738818
• 关键词: Tumour; metabolic; immune; landscape; spatial

Bacterial cancer therapy (BCT) is a promising and versatile therapeutic for solidtumours. Salmonella enterica Typhimurium (STm) is the most well-studied among bacterialvectors due to advantages in ease of genetic modification, metabolic adaptation, andmotility. A longstanding paradox in the field has been the redundancy of T cells for treatmentefficacy; instead, STm BCT depends almost exclusively on innate phagocytes for tumourcontrol. Work in our lab is aiming to understand this redundancy of T cell response to BCT,with the aim of improving therapeutic efficacy and translation to the clinic. Using a range of Tcell receptor and cytokine reporter mouse models, coupled with an inducible colorectalcancer model we have been able to identify a highly targeted dysregulation of TCR signalingdynamics. Using an in vitro co-culture system we have been able to identify that thedysregulated TCR dynamics are driven by a soluble metabolite. Ongoing work, of which thisproject will form a large part of, will aim to determine which metabolite(s) are responsible forthe dysfunctional T cell response. Using state-of-the-art imaging platforms to detectlocalisation of metabolites in relation to T cell infiltrates, alongside genetic manipulation ofSTm and delivery of co-therapies, we aim to reverse T cell dysfunction in this therapy.

细菌治疗肿瘤是一种很有前途的、多用途的治疗实体瘤的方法。肠道鼠伤寒沙门氏菌（Salmonella enterica Typhimurium，STm）是研究最多的细菌载体，具有易于遗传修饰、代谢适应性和运动性等优点。该领域长期存在的一个悖论是T细胞的冗余性对治疗效果的影响;相反，STm BCT几乎完全依赖于先天性吞噬细胞来控制肿瘤。我们实验室的工作旨在了解T细胞对BCT反应的这种冗余，目的是提高治疗效果并转化为临床。使用一系列的T细胞受体和细胞因子报告小鼠模型，再加上诱导型结直肠癌模型，我们已经能够确定一个高度靶向的TCR信号转导动力学失调。使用体外共培养系统，我们已经能够确定TCR动力学失调是由可溶性代谢物驱动的。正在进行的工作，其中该项目将形成一个很大的一部分，将旨在确定哪些代谢物（S）负责功能失调的T细胞反应。使用最先进的成像平台来检测与T细胞浸润相关的代谢物的定位，以及STm的遗传操作和联合治疗的递送，我们的目标是在这种疗法中逆转T细胞功能障碍。