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

Copland, A.; Mackie, G. M.; Scarfe, L.; Lecky, D. A.; Gudgeon, N.; McQuade, R.; Ono, M.; Barthel, M.; Hardt, W.-D.; Ohno, H.; Dimeloe, S.; Bending, D.; Maslowski, K. M.

doi:10.1101/2023.01.12.523780

bioRxiv · 10.1101/2023.01.12.523780

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

Copland, A.·Mackie, G. M.·Scarfe, L.·Lecky, D. A.·Gudgeon, N.·McQuade, R.·Ono, M.·Barthel, M.·Hardt, W.-D.·Ohno, H.·Dimeloe, S.·Bending, D.·Maslowski, K. M.

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Abstract

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) reporter mice (Nr4a3-Tocky-Ifng-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-{gamma} production decoupled from TCR signalling, decreased polyfunctionality and reduced TCM 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.

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Copland, A., Mackie, G. M., Scarfe, L., Lecky, D. A., Gudgeon, N., McQuade, R., Ono, M., Barthel, M., Hardt, W.-D., Ohno, H., Dimeloe, S., Bending, D., Maslowski, K. M.. 2023-01-13. Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. https://doi.org/10.1101/2023.01.12.523780

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