| First Author | Copland A | Year | 2024 |
| Journal | EMBO Mol Med | Volume | 16 |
| Issue | 12 | Pages | 3057-3088 |
| PubMed ID | 39558103 | Mgi Jnum | J:359568 |
| Mgi Id | MGI:7787424 | Doi | 10.1038/s44321-024-00159-2 |
| Citation | Copland A, et al. (2024) Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity. EMBO Mol Med 16(12):3057-3088 |
| abstractText | 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 IFNgamma reporter mice (Nr4a3-Tocky-Ifngamma-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-gamma 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. |
