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

• Published in: Nature communications 2022-02, Vol.13 (1), p.878-878, Article 878
• Main Authors: Singh, Alok Kumar, Praharaj, Monali, Lombardo, Kara A., Yoshida, Takahiro, Matoso, Andres, Baras, Alex S., Zhao, Liang, Srikrishna, Geetha, Huang, Joy, Prasad, Pankaj, Powell, Jonathan D., Kates, Max, McConkey, David, Pardoll, Drew M., Bishai, William R., Bivalacqua, Trinity J.
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/31; 14; 14/19; 42; 631/250/2520; 631/250/262/2106; 631/250/580; 631/250/590/1867; 64; 64/60; AMP; Animals; Anticancer properties; Antitumor activity; BCG Vaccine - immunology; Bladder; Bladder cancer; Cancer; Cancer Vaccines - immunology; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Cytokines; Cytokines - biosynthesis; Cytokines - immunology; Dinucleoside Phosphates - biosynthesis; Dinucleoside Phosphates - genetics; Dinucleoside Phosphates - immunology; Engineers; Epigenetics; Humanities and Social Sciences; Humans; Immune response; Immune system; Immunity; Immunity, Innate - immunology; Inflammation; Interferon; Macrophages - immunology; Membrane Proteins - metabolism; Metabolomics; Mice; multidisciplinary; Myeloid Cells - immunology; Pathogen-Associated Molecular Pattern Molecules - immunology; Priming; Rats; Reengineering; Science; Science (multidisciplinary); Stimulators; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - therapy; Urothelium - pathology; Vaccination; Vaccines; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28509-z

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. Vaccination with BCG has been shown to induce a pre-priming effect in innate immune cells termed trained immunity. Here the authors re-engineer the BCG vaccine and show augmented immune responses, enhanced induction of trained immunity and improved antitumor efficacy in pre-clinical models of bladder cancer.