Autophagy Controls BCG-Induced Trained Immunity and the Response to Intravesical BCG Therapy for Bladder Cancer

TLDR

BCG, the most widely used anti‑tuberculosis vaccine, also elicits non‑specific protective effects against malignancies and infections, thought to arise from epigenetic reprogramming of monocytes—trained immunity. This study investigates whether autophagy is required for BCG‑induced trained immunity. Inhibition of autophagy, pharmacologically or genetically, abolishes BCG‑induced trained immunity and H3K4 trimethylation, while SNPs in ATG2B and ATG5 modulate this response and ATG2B rs3759601 associates with bladder cancer progression after intravesical BCG therapy, underscoring autophagy’s central role.

Abstract

The anti-tuberculosis-vaccine Bacillus Calmette-Guérin (BCG) is the most widely used vaccine in the world. In addition to its effects against tuberculosis, BCG vaccination also induces non-specific beneficial effects against certain forms of malignancy and against infections with unrelated pathogens. It has been recently proposed that the non-specific effects of BCG are mediated through epigenetic reprogramming of monocytes, a process called trained immunity. In the present study we demonstrate that autophagy contributes to trained immunity induced by BCG. Pharmacologic inhibition of autophagy blocked trained immunity induced in vitro by stimuli such as β-glucans or BCG. Single nucleotide polymorphisms (SNPs) in the autophagy genes ATG2B (rs3759601) and ATG5 (rs2245214) influenced both the in vitro and in vivo training effect of BCG upon restimulation with unrelated bacterial or fungal stimuli. Furthermore, pharmacologic or genetic inhibition of autophagy blocked epigenetic reprogramming of monocytes at the level of H3K4 trimethylation. Finally, we demonstrate that rs3759601 in ATG2B correlates with progression and recurrence of bladder cancer after BCG intravesical instillation therapy. These findings identify a key role of autophagy for the nonspecific protective effects of BCG.