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

细菌肿瘤治疗(BCT)是治疗实体肿瘤的一种很有前途的、用途广泛的治疗方法。鼠伤寒沙门氏菌(STM)是目前研究最多的细菌载体之一，具有易于遗传修饰、代谢适应和运动能力强等优点。该领域长期存在的一个悖论是T细胞在治疗效果上的冗余；相反，STM BCT几乎完全依赖于天然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反应的这种冗余性，目的是提高治疗效果并转化为临床。使用一系列T细胞受体和细胞因子报告鼠模型，再加上可诱导的结直肠癌模型，我们已经能够识别TCR信号动力学的高度靶向性失调。使用体外共培养系统，我们已经能够确定失调的TCR动力学是由一种可溶性代谢物驱动的。正在进行的工作，其中这个项目将构成很大一部分，将旨在确定哪种代谢物(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细胞渗透相关的代谢物的定位，以及STm的遗传操作和协同治疗的交付，我们的目标是在这种治疗中逆转T细胞功能障碍。

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.