Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.

PLoS Pathog
Authors
Keywords
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.

Year of Publication
2014
Journal
PLoS Pathog
Volume
10
Issue
10
Pages
e1004485
Date Published
2014 Oct
ISSN
1553-7374
URL
DOI
10.1371/journal.ppat.1004485
PubMed ID
25356988
PubMed Central ID
PMC4214925
Links
Grant list
U19 AI109725 / AI / NIAID NIH HHS / United States