Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.

Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (T_CM) formation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector. Synopsis: Attenuated Salmonella show promise as cancer therapeutics, yet T cells play no role in efficacy, limiting combined checkpoint blockade therapies or induction of immune memory. Improving T cell responses requires a better understanding of the causes of T cell dysfunction during Salmonella BCT. Attenuated Salmonella enterica Typhimurium (STm) cancer therapy drives T cell dysfunction. STm depletes asparagine via an asparaginase (ansB) in the tumour microenvironment (TME), suppressing tumour growth. Asparagine depletion in the TME triggers T cell metabolic arrest by destabilising c-Myc. An STm^∆ansB mutant restores T cell function but at the cost of enhanced tumour metabolism. The STm^∆ansB mutant still effectively reduces tumour growth in a mouse model. Attenuated Salmonella show promise as cancer therapeutics, yet T cells play no role in efficacy, limiting combined checkpoint blockade therapies or induction of immune memory. Improving T cell responses requires a better understanding of the causes of T cell dysfunction during Salmonella BCT. [ABSTRACT FROM AUTHOR]