Immunotherapies specifically support or activate the body's own immune cells to seek out and attack cancer cells. For example, so-called checkpoint inhibitors are used, which specifically target "brakes" in the immune system. The efficacy of checkpoint inhibitor therapies, such as the one targeting the PD-1/PD-L1 pathway, relies on the ability to generate specific T cell activity. However, in order to be as effective as possible, such anti-PD-L1 therapies require a special microenvironment. Therefore, the availability of a large amount of the amino acid L-arginine in tumors is a key determinant of an efficient anti-tumor T cell response. 

The goal of Camilla Basso, Fernando Pablo Canale and Roger Geiger was to develop effective means to locally increase L-arginine concentrations in tumors to improve cancer therapy. For this they modified genetically a non-pathogenic strain of the bacteria E. coli to produce continuously high local concentrations of arginine in the tumour. The injections of these bacteria in the tumors and the colonization of tumors with the microbes raised the arginine concentrations, increased the number of tumor-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the destruction of tumors. 

In this study, the researchers showed a first example of how the metabolic milieu in tumors can be effectively and continuously modulated in favor of an effective anti-tumor T cell response. This bacteria-based therapy might be suitable for the development of human therapeutics.

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, Roger Geiger. Nature. 2021 Oct;598(7882):662-666.
* Contributed equally.