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.
Nature communications. 2022 Feb 15*** epublish ***
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, David McConkey, Drew M Pardoll, William R Bishai, Trinity J Bivalacqua
Johns Hopkins University, School of Medicine, Department of Medicine, Center for Tuberculosis Research, Baltimore, MD, USA., Johns Hopkins University, School of Medicine, Department of Urology, Baltimore, MD, USA., Department of Urology, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, 6620918, Japan., Department of Pathology, The Johns Hopkins University, Baltimore, MD, USA., The Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins, Baltimore, MD, USA., Johns Hopkins University, School of Medicine, Department of Medicine, Center for Tuberculosis Research, Baltimore, MD, USA. ., Perelman School of Medicine at the University of Pennsylvania, Division of Urology, Department of Surgery, Philadelphia, PA, USA. .