title: Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer.
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.
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Buffen
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jessica
authors.initials: J
authors.lastname: Quintin
authors.affiliation: The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Aylwin
authors.initials: A
authors.lastname: Ng
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Johanneke
authors.initials: J
authors.lastname: Kleinnijenhuis
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Grotenhuis
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen, The Netherlands; Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Health Sciences (RIHS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
authors.affiliation: Department of Medicine, University of Crete, Heraklion, Crete, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Chamilos
authors.affiliation: The Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, United States of America; Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Institute of Molecular Life Sciences (RIMLS), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use; D000283:Administration, Intravesical; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001343:Autophagy / Q000235:genetics / Q000276:immunology; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D001500:BCG Vaccine / Q000008:administration & dosage / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009000:Monocytes / Q000276:immunology; D009163:Mycobacterium bovis / Q000276:immunology*; D009364:Neoplasm Recurrence, Local; D020641:Polymorphism, Single Nucleotide; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D014611:Vaccination; D033921:Vesicular Transport Proteins / Q000235:genetics; D047071:beta-Glucans / Q000378:metabolism
chemical_list: C572313:ATG2B protein, human; C502778:ATG5 protein, human; D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D000071187:Autophagy-Related Protein 5; D000071183:Autophagy-Related Proteins; D001500:BCG Vaccine; D016207:Cytokines; D008869:Microtubule-Associated Proteins; D033921:Vesicular Transport Proteins; D047071:beta-Glucans