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

• DOI: 10.1371/journal.ppat.1004485
• Publication Date: 2014-10-30T14:22:58Z
• Authors: Kathrin Buffen; Marije Oosting; Jessica Quintin; Aylwin Ng; Johanneke Kleinni...; Vinod Kumar; Esther van de Vosse; Cisca Wijmenga; Reinout van Crevel; Egbert Oosterwijk; Anne J. Grotenhuis; Sita H. Vermeulen; Lambertus A. Kiem...; Frank L. van de V...; Georgios Chamilos; Ramnik J. Xavier; Jos W. M. van der...; Mihai G. Netea; Leo A. B. Joosten
• Keywords: 0301 basic medicine; beta-Glucans; Cancer Treatment; Vesicular Transport Proteins; Autophagy-Related Proteins; Kaplan-Meier Estimate; Monocytes; Autophagy-Related Protein 5; White Blood Cells; NATURAL-KILLER-CELLS; Animal Cells; Medicine and Health Sciences; Biology (General); WEST-AFRICA; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; Innate Immune System; Vaccines; 0303 health sciences; Vaccination; Infectious Disease Immunology; Vaccination and Immunization; Bladder Cancer; Mycobacterium bovis; 3. Good health; Administration, Intravesical; Oncology; MONOCYTES; BCG Vaccine; CHILD SURVIVAL; VACCINATION; Cytokines; Immunotherapy; Cellular Types; Microtubule-Associated Proteins; Research Article; Attenuated Vaccines; Radboudumc 15: Urological cancers RIMLS: Radboud Institute for Molecular Life Sciences; QH301-705.5; Immune Cells; Urology; Immunology; Antineoplastic Agents; Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; DENDRITIC CELLS; Polymorphism, Single Nucleotide; Cancer Immunotherapy; Immune Activation; Immunomodulation; 618; 03 medical and health sciences; HOST-DEFENSE; Adjuvants, Immunologic; 616; Autophagy; Humans; IMMUNOTHERAPY; CANDIDA-ALBICANS; Blood Cells; Interleukins; Immunity; Biology and Life Sciences; Cancers and Neoplasms; Cell Biology; Molecular Development; RC581-607; Radboudumc 9: Rare cancers RIMLS: Radboud Institute for Molecular Life Sciences; RANDOMIZED-TRIAL; Genitourinary Tract Tumors; Urinary Bladder Neoplasms; 13. Climate action; Immune System; Radboudumc 5: Inflammatory diseases RIHS: Radboud Institute for Health Sciences; Clinical Immunology; Immunologic diseases. Allergy; Neoplasm Recurrence, Local; Developmental Biology

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.