Recombinant BCG overexpressing a STING agonist elicits trained immunity and improved antitumor efficacy in non-muscle invasive bladder cancer

Abstract

ABSTRACTBCG 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.SIGNIFICANCEThis study demonstrates that the antitumor efficacy of BCG during bladder cancer is mediated via myeloid cell “training” in which BCG leads to epigenetic modifications accompanied by metabolic and cellular reprogramming changes which promote antitumor immunity. Using a recombinant BCG strain which delivers high levels of a STING agonist, we further demonstrate that STING pathway stimulation strongly enhances myeloid cell training as well as antitumor potency.