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

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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.