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Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer

Author

Listed:
  • Alok Kumar Singh

    (Center for Tuberculosis Research)

  • Monali Praharaj

    (Center for Tuberculosis Research
    The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins)

  • Kara A. Lombardo

    (Johns Hopkins University, School of Medicine, Department of Urology)

  • Takahiro Yoshida

    (Hyogo Prefectural Nishinomiya Hospital)

  • Andres Matoso

    (The Johns Hopkins University)

  • Alex S. Baras

    (The Johns Hopkins University)

  • Liang Zhao

    (The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins)

  • Geetha Srikrishna

    (Center for Tuberculosis Research)

  • Joy Huang

    (Center for Tuberculosis Research)

  • Pankaj Prasad

    (Center for Tuberculosis Research)

  • Jonathan D. Powell

    (The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins)

  • Max Kates

    (Johns Hopkins University, School of Medicine, Department of Urology)

  • David McConkey

    (Johns Hopkins University, School of Medicine, Department of Urology)

  • Drew M. Pardoll

    (The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins)

  • William R. Bishai

    (Center for Tuberculosis Research)

  • Trinity J. Bivalacqua

    (Perelman School of Medicine at the University of Pennsylvania, Division of Urology, Department of Surgery)

Abstract

In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING). We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher pro-inflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhances epigenetic and metabolomic changes. In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality. These results indicate that trained immunity levels and antitumor efficacy may be increased by modifying BCG to express higher levels of key PAMP molecules.

Suggested Citation

  • Alok Kumar Singh & Monali Praharaj & Kara A. Lombardo & Takahiro Yoshida & Andres Matoso & Alex S. Baras & Liang Zhao & Geetha Srikrishna & Joy Huang & Pankaj Prasad & Jonathan D. Powell & Max Kates &, 2022. "Re-engineered BCG overexpressing cyclic di-AMP augments trained immunity and exhibits improved efficacy against bladder cancer," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28509-z
    DOI: 10.1038/s41467-022-28509-z
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