Metabolic modulation of tumours with engineered bacteria for immunotherapy

Fernando P. Canale, Camilla Basso, Gaia Antonini, Michela Perotti, Ning Li, Anna Sokolovska, Julia Neumann, Michael J. James, Stefania Geiger, Wenjie Jin, Jean-Philippe Theurillat, Kip A. West, Daniel S. Leventhal, Jose M. Lora, Federica Sallusto and Roger Geiger ()
Additional contact information
Fernando P. Canale: Università della Svizzera italiana
Camilla Basso: Università della Svizzera italiana
Gaia Antonini: Università della Svizzera italiana
Michela Perotti: Università della Svizzera italiana
Ning Li: Synlogic
Anna Sokolovska: Synlogic
Julia Neumann: Università della Svizzera italiana
Michael J. James: Synlogic
Stefania Geiger: Università della Svizzera italiana
Wenjie Jin: Università della Svizzera italiana
Jean-Philippe Theurillat: Università della Svizzera italiana
Kip A. West: Synlogic
Daniel S. Leventhal: Synlogic
Jose M. Lora: Synlogic
Federica Sallusto: Università della Svizzera italiana
Roger Geiger: Università della Svizzera italiana

Nature, 2021, vol. 598, issue 7882, 662-666

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-04003-2

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