Metabolic modulation of tumours with engineered bacteria for immunotherapy

The availability of l -arginine in tumours is a key determinant of an efficient anti-tumour T cell response 1 – 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 antibodies 5 . 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 6 , 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.