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Metabolic modulation of tumours with engineered bacteria for immunotherapy

Author

Listed:
  • Fernando P. Canale

    (Università della Svizzera italiana)

  • Camilla Basso

    (Università della Svizzera italiana
    Università della Svizzera italiana)

  • Gaia Antonini

    (Università della Svizzera italiana)

  • Michela Perotti

    (Università della Svizzera italiana
    ETH Zürich)

  • 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
    ETH Zürich)

  • Jean-Philippe Theurillat

    (Università della Svizzera italiana)

  • Kip A. West

    (Synlogic)

  • Daniel S. Leventhal

    (Synlogic)

  • Jose M. Lora

    (Synlogic
    Intergalactic Therapeutics)

  • Federica Sallusto

    (Università della Svizzera italiana
    ETH Zürich)

  • Roger Geiger

    (Università della Svizzera italiana
    Università della Svizzera italiana)

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.

Suggested Citation

  • 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. W, 2021. "Metabolic modulation of tumours with engineered bacteria for immunotherapy," Nature, Nature, vol. 598(7882), pages 662-666, October.
  • Handle: RePEc:nat:nature:v:598:y:2021:i:7882:d:10.1038_s41586-021-04003-2
    DOI: 10.1038/s41586-021-04003-2
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    Cited by:

    1. Jae Sung Cho & Dongsoo Yang & Cindy Pricilia Surya Prabowo & Mohammad Rifqi Ghiffary & Taehee Han & Kyeong Rok Choi & Cheon Woo Moon & Hengrui Zhou & Jae Yong Ryu & Hyun Uk Kim & Sang Yup Lee, 2023. "Targeted and high-throughput gene knockdown in diverse bacteria using synthetic sRNAs," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Yi Zhang & Mingjie Wang & Ling Ye & Shengqi Shen & Yuxi Zhang & Xiaoyu Qian & Tong Zhang & Mengqiu Yuan & Zijian Ye & Jin Cai & Xiang Meng & Shiqiao Qiu & Shengzhi Liu & Rui Liu & Weidong Jia & Xianzh, 2024. "HKDC1 promotes tumor immune evasion in hepatocellular carcinoma by coupling cytoskeleton to STAT1 activation and PD-L1 expression," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Mairead K. Heavey & Anthony Hazelton & Yuyan Wang & Mitzy Garner & Aaron C. Anselmo & Janelle C. Arthur & Juliane Nguyen, 2024. "Targeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix enhances gut residence time and recovery in murine colitis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Ling Huang & Wei Tang & Lina He & Mengke Li & Xian Lin & Ao Hu & Xindi Huang & Zhouyu Wu & Zhiyong Wu & Shiyun Chen & Yangbo Hu, 2024. "Engineered probiotic Escherichia coli elicits immediate and long-term protection against influenza A virus in mice," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    5. Dinh-Huy Nguyen & Ari Chong & Yeongjin Hong & Jung-Joon Min, 2023. "Bioengineering of bacteria for cancer immunotherapy," Nature Communications, Nature, vol. 14(1), pages 1-5, December.

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