BCG remains first-line therapy for non-muscle invasive bladder cancer (NIMBC) but its mechanism of action is not fully understood nor is its efficacy complete. We engineered a recombinant BCG (BCG-STING) that releases increased levels the STING agonist, c-di-AMP. Compared with BCG, BCG-STING demonstrated superior antitumor efficacy in models of NMIBC, more potent pro-inflammatory cytokine responses, greater myeloid cell reprogramming (M1 shift) associated with enhanced epigenetic and metabolomic changes and enhanced Teffector infiltration, all favoring antitumor immunity. These findings support the local induction by BCG-STING of enhanced and remodeled innate immune responses, sometimes termed trained immunity, and ultimately enhanced T cell immunity. They reveal that STING pathway activation is a proximal trigger in trained immunity remodeling, which may be a central mechanism for both BCG and BCG-STING antitumor activity in NMIBC.
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Immunology and Microbiology(all)
- Pharmacology, Toxicology and Pharmaceutics(all)