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Metabolic modulation of tumours with engineered bacteria for immunotherapy.

Fernando P CanaleCamilla BassoGaia AntoniniMichela PerottiNing LiAnna SokolovskaJulia NeumannMichael J JamesStefania GeigerWenjie JinJean-Philippe TheurillatKip A WestDaniel S LeventhalJose M LoraFederica SallustoRoger Geiger
Published in: Nature (2021)
The availability of L-arginine in tumours is a key determinant of an efficient anti-tumour T cell response1-4. Consequently, increases of typically low L-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies5. However, currently no means are available to locally increase intratumoural L-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours6, to L-arginine. Colonization of tumours with these bacteria increased intratumoural L-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.
Keyphrases
  • nitric oxide
  • escherichia coli
  • amino acid
  • stem cells
  • microbial community
  • risk assessment
  • multidrug resistant
  • ionic liquid
  • room temperature
  • anaerobic digestion
  • drug delivery
  • candida albicans