Metabolic modulation of tumours with engineered bacteria for immunotherapy

FP Canale, C Basso, G Antonini, M Perotti, N Li… - Nature, 2021 - nature.com
FP Canale, C Basso, G Antonini, M Perotti, N Li, A Sokolovska, J Neumann, MJ James…
Nature, 2021nature.com
The availability of l-arginine in tumours is a key determinant of an efficient anti-tumour T cell
response,,–. 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 antibodies. 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 …
Abstract
The availability of l-arginine in tumours is a key determinant of an efficient anti-tumour T cell response, , –. 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 antibodies. 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 tumours, 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.
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