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Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer

Nature Reviews Urology volume 17, pages 513–525 (2020)Cite this article

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Abstract

Intravesical BCG instillation is the gold-standard adjuvant immunotherapy for patients with high-risk non-muscle-invasive bladder cancer. However, the precise mechanism of action by which BCG asserts its beneficial effects is still unclear. BCG has been shown to induce a non-specific enhancement of the biological function in cells of the innate immune system, creating a de facto heterologous immunological memory that has been termed trained immunity. Trained immunity or innate immune memory enables innate immune cells to mount a more robust response to secondary non-related stimuli after being initially primed (or trained) by a challenge such as BCG. BCG-induced trained immunity is characterized by the metabolic rewiring of monocyte intracellular metabolism and epigenetic modifications, which subsequently lead to functional reprogramming effects, such as an increased production of cytokines, on restimulation. Results from BCG vaccination studies in humans show that trained immunity might at least partly account for the heterologous beneficial effects of BCG vaccination. Additionally, immunity might have a role in the effect of BCG immunotherapy for bladder cancer. Based on these indications, we propose that trained immunity could be one of the important mechanisms mediating BCG immunotherapy and could provide a basis for further improvements towards a personalized approach to BCG therapy in non-muscle-invasive bladder cancer.

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Fig. 1: A proposed mechanism of BCG-induced trained immunity in the urothelium.
Fig. 2: Long-term systemic induction of trained immunity.
Fig. 3: BCG-trained cells increase cytotoxic leukocyte responses.

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References

  1. Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary bacillus Calmette–Guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).

    CAS  PubMed  Google Scholar 

  2. Power, N. E. & Izawa, J. Comparison of guidelines on non-muscle invasive bladder cancer (EAU, CUA, AUA, NCCN, NICE). Bladder Cancer 2, 27–36 (2016).

    PubMed  PubMed Central  Google Scholar 

  3. Babjuk, M. et al. European association of urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) — 2019 update. Eur. Urol. 76, 639–657 (2019).

    CAS  PubMed  Google Scholar 

  4. Shelley, M. D. et al. A systematic review of intravesical bacillus Calmette–Guerin plus transurethral resection vs transurethral resection alone in Ta and T1 bladder cancer. BJU Int. 88, 209–216 (2001).

    CAS  PubMed  Google Scholar 

  5. Shelley, M. D. et al. Intravesical bacillus Calmette–Guerin is superior to mitomycin C in reducing tumour recurrence in high-risk superficial bladder cancer: a meta-analysis of randomized trials. BJU Int. 93, 485–490 (2004).

    CAS  PubMed  Google Scholar 

  6. Sylvester, R. J., van der Meijden, A. P., Witjes, J. A. & Kurth, K. Bacillus Calmette–Guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J. Urol. 174, 86–91 (2005).

    CAS  PubMed  Google Scholar 

  7. Sylvester, R. J., van der, M. A. & Lamm, D. L. Intravesical bacillus Calmette–Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J. Urol. 168, 1964–1970 (2002).

    CAS  PubMed  Google Scholar 

  8. Han, R. F. & Pan, J. G. Can intravesical bacillus Calmette–Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 67, 1216–1223 (2006).

    PubMed  Google Scholar 

  9. Cambier, S. et al. EORTC nomograms and risk groups for predicting recurrence, progression, and disease-specific and overall survival in non-muscle-invasive stage Ta–T1 urothelial bladder cancer patients treated with 1–3 years of maintenance bacillus Calmette–Guerin. Eur. Urol. 69, 60–69 (2016).

    PubMed  Google Scholar 

  10. Hemdan, T. et al. 5-Year outcome of a randomized prospective study comparing bacillus Calmette–Guerin with epirubicin and interferon-alpha2b in patients with T1 bladder cancer. J. Urol. 191, 1244–1249 (2014).

    CAS  PubMed  Google Scholar 

  11. Redelman-Sidi, G., Glickman, M. S. & Bochner, B. H. The mechanism of action of BCG therapy for bladder cancer — a current perspective. Nat. Rev. Urol. 11, 153–162 (2014).

    CAS  PubMed  Google Scholar 

  12. Pettenati, C. & Ingersoll, M. A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 15, 615–625 (2018).

    CAS  PubMed  Google Scholar 

  13. Jallad, S., Goubet, S., Symes, A., Larner, T. & Thomas, P. Prognostic value of inflammation or granuloma after intravesical BCG in non-muscle-invasive bladder cancer. BJU Int. 113, E22–E27 (2014).

    PubMed  Google Scholar 

  14. Pieras-Ayala, E. et al. Prognostic value of cystocopically pseudotumoral lesions (inflammation/granuloma) in primary stage T1 grade 3 bladder tumors treated with BCG. Int. Urol. Nephrol. 33, 469–472 (2001).

    CAS  PubMed  Google Scholar 

  15. Bisiaux, A. et al. Molecular analyte profiling of the early events and tissue conditioning following intravesical bacillus Calmette–Guerin therapy in patients with superficial bladder cancer. J. Urol. 181, 1571–1580 (2009).

    CAS  PubMed  Google Scholar 

  16. Saint, F. et al. Urinary IL-2 assay for monitoring intravesical bacillus Calmette–Guerin response of superficial bladder cancer during induction course and maintenance therapy. Int. J. Cancer 107, 434–440 (2003).

    CAS  PubMed  Google Scholar 

  17. Saint, F. et al. Prognostic value of a T helper 1 urinary cytokine response after intravesical bacillus Calmette–Guerin treatment for superficial bladder cancer. J. Urol. 167, 364–367 (2002).

    PubMed  Google Scholar 

  18. Bekkering, S. et al. In vitro experimental model of trained innate immunity in human primary monocytes. Clin. Vaccine Immunol. 23, 926–933 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Cheng, S. C. et al. mTOR- and HIF-1alpha-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. van der Heijden, C. et al. Epigenetics and trained immunity. Antioxid. Redox Signal. 29, 1023–1040 (2018).

    PubMed  PubMed Central  Google Scholar 

  21. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014).

    PubMed  PubMed Central  Google Scholar 

  22. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    PubMed  PubMed Central  Google Scholar 

  23. Arts, R. J. W. et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 17, 2562–2571 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Arts, R. J. et al. Long-term in vitro and in vivo effects of gamma-irradiated BCG on innate and adaptive immunity. J. Leukoc. Biol. 98, 995–1001 (2015).

    CAS  PubMed  Google Scholar 

  25. Wang, X. et al. MLL1, a H3K4 methyltransferase, regulates the TNFalpha-stimulated activation of genes downstream of NF-kappaB. J. Cell Sci. 125, 4058–4066 (2012).

    CAS  PubMed  Google Scholar 

  26. Austenaa, L. et al. The histone methyltransferase Wbp7 controls macrophage function through GPI glycolipid anchor synthesis. Immunity 36, 572–585 (2012).

    CAS  PubMed  Google Scholar 

  27. Kimball, A. S. et al. The histone methyltransferase MLL1 directs macrophage-mediated inflammation in wound healing and is altered in a murine model of obesity and type 2 diabetes. Diabetes 66, 2459–2471 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kleinnijenhuis, J. et al. Bacille Calmette–Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA 109, 17537–17542 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Arts, R. J. et al. Vitamin A induces inhibitory histone methylation modifications and down-regulates trained immunity in human monocytes. J. Leukoc. Biol. 98, 129–136 (2015).

    CAS  PubMed  Google Scholar 

  30. Keating, S. T. & El-Osta, A. Epigenetics and metabolism. Circ. Res. 116, 715–736 (2015).

    CAS  PubMed  Google Scholar 

  31. Arts, R. J. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. 24, 807–819 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Arts, R. J. W. et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23, 89–100 (2018).

    CAS  PubMed  Google Scholar 

  33. Buffen, K. et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. 10, e1004485 (2014).

    PubMed  PubMed Central  Google Scholar 

  34. Kleinnijenhuis, J. et al. Long-lasting effects of BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity. J. Innate Immun. 6, 152–158 (2014).

    CAS  PubMed  Google Scholar 

  35. Xie, Z. & Klionsky, D. J. Autophagosome formation: core machinery and adaptations. Nat. Cell Biol. 9, 1102–1109 (2007).

    CAS  PubMed  Google Scholar 

  36. Shibutani, S. T., Saitoh, T., Nowag, H., Munz, C. & Yoshimori, T. Autophagy and autophagy-related proteins in the immune system. Nat. Immunol. 16, 1014–1024 (2015).

    CAS  PubMed  Google Scholar 

  37. Jo, E. K. Autophagy as an innate defense against mycobacteria. Pathog. Dis. 67, 108–118 (2013).

    CAS  PubMed  Google Scholar 

  38. Songane, M., Kleinnijenhuis, J., Netea, M. G. & van Crevel, R. The role of autophagy in host defence against Mycobacterium tuberculosis infection. Tuberculosis 92, 388–396 (2012).

    PubMed  Google Scholar 

  39. Zullo, A. J. & Lee, S. Mycobacterial induction of autophagy varies by species and occurs independently of mammalian target of rapamycin inhibition. J. Biol. Chem. 287, 12668–12678 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Brooks, M. N. et al. NOD2 controls the nature of the inflammatory response and subsequent fate of Mycobacterium tuberculosis and M. bovis BCG in human macrophages. Cell. Microbiol. 13, 402–418 (2011).

    CAS  PubMed  Google Scholar 

  41. Schenk, M. et al. Human NOD2 recognizes structurally unique muramyl dipeptides from Mycobacterium leprae. Infect. Immun. 84, 2429–2438 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Park, J.-H. et al. RICK/RIP2 mediates innate immune responses induced through Nod1 and Nod2 but not TLRs. J. Immunol. 178, 2380–2386 (2007).

    CAS  PubMed  Google Scholar 

  43. Bourigault, M. L. et al. Relative contribution of IL-1alpha, IL-1beta and TNF to the host response to Mycobacterium tuberculosis and attenuated M. bovis BCG. Immun. Inflamm. Dis. 1, 47–62 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190 (2018).

    CAS  PubMed  Google Scholar 

  46. King, K. Y. & Goodell, M. A. Inflammatory modulation of HSCs: viewing the HSC as a foundation for the immune response. Nat. Rev. Immunol. 11, 685–692 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wen, A. Q. et al. Effects of haplotypes in the interleukin 1beta promoter on lipopolysaccharide-induced interleukin 1beta expression. Shock 26, 25–30 (2006).

    CAS  PubMed  Google Scholar 

  48. Levine, M. I. & Sackett, M. F. Results of BCG immunization in New York City. Am. Rev. Tuberc. 53, 517–532 (1946).

    CAS  PubMed  Google Scholar 

  49. Aronson, J. D. Protective vaccination against tuberculosis, with special reference to BCG vaccine. Minn. Med. 31, 1336 (1948).

    CAS  PubMed  Google Scholar 

  50. Ferguson, R. G. & Simes, A. B. BCG vaccination of Indian infants in Saskatchewan. Tubercle 30, 5–11 (1949).

    CAS  PubMed  Google Scholar 

  51. Rosenthal, S. R. et al. BCG vaccination in tuberculous households. Am. Rev. Respir. Dis. 84, 690–704 (1961).

    CAS  PubMed  Google Scholar 

  52. Trunz, B. B., Fine, P. & Dye, C. Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness. Lancet 367, 1173–1180 (2006).

    PubMed  Google Scholar 

  53. Aaby, P. et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 204, 245–252 (2011).

    CAS  PubMed  Google Scholar 

  54. Biering-Sorensen, S. et al. Small randomized trial among low-birth-weight children receiving bacillus Calmette–Guerin vaccination at first health center contact. Pediatr. Infect. Dis. J. 31, 306–308 (2012).

    PubMed  Google Scholar 

  55. Higgins, J. P. et al. Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ 355, i5170 (2016).

    PubMed  PubMed Central  Google Scholar 

  56. Moorlag, S., Arts, R. J. W., van Crevel, R. & Netea, M. G. Non-specific effects of BCG vaccine on viral infections. Clin. Microbiol. Infect. 25, 1473–1478 (2019).

    CAS  PubMed  Google Scholar 

  57. Walk, J. et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 10, 874 (2019).

    PubMed  PubMed Central  Google Scholar 

  58. Kleinnijenhuis, J. et al. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin. Immunol. 155, 213–219 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. van ‘t Wout, J. W., Poell, R. & van Furth, R. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol. 36, 713–719 (1992).

    PubMed  Google Scholar 

  60. Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375–388 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Conti, P. et al. Bacillus Calmette–Guerin potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients. Cancer Immunol. Immunother. 38, 365–371 (1994).

    CAS  PubMed  Google Scholar 

  62. Kim, C. I., Shin, J. S., Kim, H. I., Lee, J. M. & Kim, S. J. Production of tumor necrosis factor by intravesical administration of bacillus Calmette–Guerin in patients with superficial bladder cancer. Yonsei Med. J. 34, 356–364 (1993).

    CAS  PubMed  Google Scholar 

  63. Calais da Silva, F. M. et al. Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more. J. Cancer Metastasis Treat. 3, 116–126 (2017).

    Google Scholar 

  64. Adeli, K. et al. Complex biological profile of hematologic markers across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures survey. Clin. Chem. 61, 1075–1086 (2015).

    CAS  PubMed  Google Scholar 

  65. Luo, Y., Chen, X. & O’Donnell, M. A. Mycobacterium bovis bacillus Calmette–Guerin (BCG) induces human CC- and CXC-chemokines in vitro and in vivo. Clin. Exp. Immunol. 147, 370–378 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Noguera-Ortega, E. et al. Intravesical Mycobacterium brumae triggers both local and systemic immunotherapeutic responses against bladder cancer in mice. Sci. Rep. 8, 15102 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. Biot, C. et al. Preexisting BCG-specific T cells improve intravesical immunotherapy for bladder cancer. Sci. Transl Med. 4, 137ra172 (2012).

    Google Scholar 

  68. Shintani, Y. et al. Intravesical instillation therapy with bacillus Calmette–Guerin for superficial bladder cancer: study of the mechanism of bacillus Calmette–Guerin immunotherapy. Int. J. Urol. 14, 140–146 (2007).

    CAS  PubMed  Google Scholar 

  69. Taniguchi, K. et al. Systemic immune response after intravesical instillation of bacille Calmette–Guerin (BCG) for superficial bladder cancer. Clin. Exp. Immunol. 115, 131–135 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kamat, A. M. et al. Cytokine panel for response to intravesical therapy (CyPRIT): nomogram of changes in urinary cytokine levels predicts patient response to bacillus Calmette–Guerin. Eur. Urol. 69, 197–200 (2016).

    CAS  PubMed  Google Scholar 

  71. de Reijke, T. M., de Boer, E. C., Kurth, K. H. & Schamhart, D. H. Urinary cytokines during intravesical bacillus Calmette–Guerin therapy for superficial bladder cancer: processing, stability and prognostic value. J. Urol. 155, 477–482 (1996).

    PubMed  Google Scholar 

  72. de Reijke, T. M., De Boer, E. C., Kurth, K. H. & Schamhart, D. H. Urinary interleukin-2 monitoring during prolonged bacillus Calmette–Guerin treatment: can it predict the optimal number of instillations? J. Urol. 161, 67–71 (1999).

    PubMed  Google Scholar 

  73. Reale, M. et al. Production of MCP-1 and RANTES in bladder cancer patients after bacillus Calmette–Guerin immunotherapy. Cancer Immunol. Immunother. 51, 91–98 (2002).

    CAS  PubMed  Google Scholar 

  74. Arends, T. J. H. et al. Urinary cytokines in patients treated with intravesical mitomycin-C with and without hyperthermia. World J. Urol. 33, 1411–1417 (2015).

    CAS  PubMed  Google Scholar 

  75. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    CAS  PubMed  Google Scholar 

  76. Toyonaga, K. et al. C-type lectin receptor DCAR recognizes mycobacterial phosphatidyl-inositol mannosides to promote a Th1 response during infection. Immunity 45, 1245–1257 (2016).

    CAS  PubMed  Google Scholar 

  77. Torrelles, J. B., Azad, A. K. & Schlesinger, L. S. Fine discrimination in the recognition of individual species of phosphatidyl-myo-inositol mannosides from Mycobacterium tuberculosis by C-type lectin pattern recognition receptors. J. Immunol. 177, 1805–1816 (2006).

    CAS  PubMed  Google Scholar 

  78. Yonekawa, A. et al. Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria. Immunity 41, 402–413 (2014).

    CAS  PubMed  Google Scholar 

  79. Ishikawa, E., Mori, D. & Yamasaki, S. Recognition of mycobacterial lipids by immune receptors. Trends Immunol. 38, 66–76 (2017).

    CAS  PubMed  Google Scholar 

  80. Jones, B. W., Heldwein, K. A., Means, T. K., Saukkonen, J. J. & Fenton, M. J. Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages. Ann. Rheumatic Dis. 60, iii6–iii12 (2001).

    CAS  Google Scholar 

  81. Jones, B. W. et al. Different Toll-like receptor agonists induce distinct macrophage responses. J. Leukoc. Biol. 69, 1036–1044 (2001).

    CAS  PubMed  Google Scholar 

  82. Yan, R. & Liu, Z. LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation. Protein Cell 8, 55–66 (2017).

    CAS  PubMed  Google Scholar 

  83. de Jong, E., Lim, A., Waterer, G. & Price, P. Monocyte-derived macrophages do not explain susceptibility to pulmonary non-tuberculous mycobacterial disease. Clin. Transl Immunol. 1, e2 (2012).

    Google Scholar 

  84. Latz, E. et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat. Immunol. 5, 190–198 (2004).

    CAS  PubMed  Google Scholar 

  85. Lee, K. W. et al. Immunostimulatory oligodeoxynucleotide isolated from genome wide screening of Mycobacterium bovis chromosomal DNA. Mol. Immunol. 43, 2107–2118 (2006).

    CAS  PubMed  Google Scholar 

  86. Thomas-White, K. et al. Culturing of female bladder bacteria reveals an interconnected urogenital microbiota. Nat. Commun. 9, 1557 (2018).

    PubMed  PubMed Central  Google Scholar 

  87. Meshkibaf, S., Fritz, J., Gottschalk, M. & Kim, S. O. Preferential production of G-CSF by a protein-like Lactobacillus rhamnosus GR-1 secretory factor through activating TLR2-dependent signaling events without activation of JNKs. BMC Microbiol. 15, 238 (2015).

    PubMed  PubMed Central  Google Scholar 

  88. Uehori, J. et al. Simultaneous blocking of human Toll-like receptors 2 and 4 suppresses myeloid dendritic cell activation induced by Mycobacterium bovis bacillus Calmette–Guerin peptidoglycan. Infect. Immun. 71, 4238–4249 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Tsuji, S. et al. Maturation of human dendritic cells by cell wall skeleton of Mycobacterium bovis bacillus Calmette–Guerin: involvement of Toll-like receptors. Infect. Immun. 68, 6883–6890 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Astarie-Dequeker, C. et al. Phthiocerol dimycocerosates of M. tuberculosis participate in macrophage invasion by inducing changes in the organization of plasma membrane lipids. PLoS Pathog. 5, e1000289 (2009).

    PubMed  PubMed Central  Google Scholar 

  91. Oldenburg, R. et al. Mycobacterial phenolic glycolipids selectively disable TRIF-dependent TLR4 signaling in macrophages. Front. Immunol. 9, 2 (2018).

    PubMed  PubMed Central  Google Scholar 

  92. Arbues, A. et al. Trisaccharides of phenolic glycolipids confer advantages to pathogenic mycobacteria through manipulation of host–cell pattern-recognition receptors. ACS Chem. Biol. 11, 2865–2875 (2016).

    CAS  PubMed  Google Scholar 

  93. Kohka Takahashi, H. et al. Role of cell–cell interactions in high mobility group Box 1 cytokine activity in human peripheral blood mononuclear cells and mouse splenocytes. Eur. J. Pharmacol. 701, 194–202 (2013).

    PubMed  Google Scholar 

  94. Andersson, U. et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Aneja, R. K. et al. Preconditioning with high mobility group Box 1 (HMGB1) induces lipopolysaccharide (LPS) tolerance. J. Leukoc. Biol. 84, 1326–1334 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Zhang, G. et al. HMGB1 release by urothelial carcinoma cells in response to bacillus Calmette–Guerin functions as a paracrine factor to potentiate the direct cellular effects of bacillus Calmette–Guerin. J. Urol. 190, 1076–1082 (2013).

    CAS  PubMed  Google Scholar 

  97. Zhang, G., Chen, F., Cao, Y. & See, W. A. Contributors to HMGB1 release by urothelial carcinoma cells in response to bacillus Calmette–Guerin. J. Urol. 190, 1398–1403 (2013).

    CAS  PubMed  Google Scholar 

  98. Shah, G. et al. The dose–response relationship of bacillus Calmette–Guerin and urothelial carcinoma cell biology. J. Urol. 195, 1903–1910 (2016).

    PubMed  Google Scholar 

  99. See, W. A. et al. Bacille Calmette–Guerin induces caspase-independent cell death in urothelial carcinoma cells together with release of the necrosis-associated chemokine high molecular group Box protein 1. BJU Int. 103, 1714–1720 (2009).

    PubMed  Google Scholar 

  100. Chen, B. et al. S100A9 induced inflammatory responses are mediated by distinct damage associated molecular patterns (DAMP) receptors in vitro and in vivo. PLoS One 10, e0115828 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Tolson, J. P. et al. Differential detection of S100A8 in transitional cell carcinoma of the bladder by pair wise tissue proteomic and immunohistochemical analysis. Proteomics 6, 697–708 (2006).

    CAS  PubMed  Google Scholar 

  102. Afonina, I. S. et al. Granzyme B-dependent proteolysis acts as a switch to enhance the proinflammatory activity of IL-1alpha. Mol. Cell 44, 265–278 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Di Paolo, N. C. & Shayakhmetov, D. M. Interleukin 1alpha and the inflammatory process. Nat. Immunol. 17, 906–913 (2016).

    PubMed  PubMed Central  Google Scholar 

  104. Grimm, S. et al. Malignancy of bladder cancer cells is enhanced by tumor-associated fibroblasts through a multifaceted cytokine–chemokine loop. Exp. Cell Res. 335, 1–11 (2015).

    CAS  PubMed  Google Scholar 

  105. Garg, M. et al. Heat-shock protein 70-2 (HSP70-2) expression in bladder urothelial carcinoma is associated with tumour progression and promotes migration and invasion. Eur. J. Cancer 46, 207–215 (2010).

    CAS  PubMed  Google Scholar 

  106. Behnsawy, H. M., Miyake, H., Kusuda, Y. & Fujisawa, M. Small interfering RNA targeting heat shock protein 70 enhances chemosensitivity in human bladder cancer cells. Urologic Oncol. 31, 843–848 (2013).

    CAS  Google Scholar 

  107. Vabulas, R. M. et al. HSP70 as endogenous stimulus of the Toll/interleukin-1 receptor signal pathway. J. Biol. Chem. 277, 15107–15112 (2002).

    CAS  PubMed  Google Scholar 

  108. Fang, H. et al. Toll-like receptor 4 (TLR4) is essential for Hsp70-like protein 1 (HSP70L1) to activate dendritic cells and induce Th1 response. J. Biol. Chem. 286, 30393–30400 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Lee, K. H., Jeong, J. & Yoo, C. G. Positive feedback regulation of heat shock protein 70 (Hsp70) is mediated through Toll-like receptor 4-PI3K/Akt-glycogen synthase kinase-3beta pathway. Exp. Cell Res. 319, 88–95 (2013).

    CAS  PubMed  Google Scholar 

  110. Yang Han, Z. & Oppenheim, J. J. Alarmins and immunity. Immunol. Rev. 280, 41–56 (2017).

    Google Scholar 

  111. Daniels, M. J. et al. Contemporary oncologic outcomes of second induction course BCG in patients with nonmuscle invasive bladder cancer. Urologic Oncol. 38, 5 (2020).

    Google Scholar 

  112. Grimm, M. O. et al. Treatment of high-grade non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: results of the European Association of Urology Research Foundation randomised phase III clinical trial ‘NIMBUS’. Eur. Urol. https://doi.org/10.1016/j.eururo.2020.04.066 (2020).

    Article  PubMed  Google Scholar 

  113. Oddens, J. et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette–Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur. Urol. 63, 462–472 (2013).

    PubMed  Google Scholar 

  114. Kamat, A. M. et al. Expert consensus document: consensus statement on best practice management regarding the use of intravesical immunotherapy with BCG for bladder cancer. Nat. Rev. Urol. 12, 225–235 (2015).

    PubMed  Google Scholar 

  115. D’Andrea, D. et al. Comparative effectiveness of intravesical BCG-Tice and BCG-Moreau in patients with non-muscle-invasive bladder cancer. Clin. Genitourin. Cancer 18, 20–25 (2020).

    PubMed  Google Scholar 

  116. Niwa, N. et al. Does switching the bacillus Calmette–Guerin strain affect clinical outcome in patients with recurrent non-muscle-invasive bladder cancer after initial bacillus Calmette–Guerin therapy? Urologic Oncol. 36, 306 (2018).

    Google Scholar 

  117. Krajewski, W. et al. Are there differences in toxicity and efficacy between various bacillus Calmette–Guerin strains in bladder cancer patients? Analysis of 844 patients. Urol. Int. 101, 277–284 (2018).

    CAS  PubMed  Google Scholar 

  118. Niwa, N. et al. Purified protein derivative skin test prior to bacillus Calmette–Guerin therapy may have therapeutic impact in patients with nonmuscle invasive bladder cancer. J. Urol. 199, 1446–1451 (2018).

    CAS  PubMed  Google Scholar 

  119. Hofbauer, S. L. et al. The Moreau strain of bacillus Calmette–Guerin (BCG) for high-risk non-muscle invasive bladder cancer: an alternative during worldwide BCG shortage? Urol. Int. 96, 46–50 (2016).

    CAS  PubMed  Google Scholar 

  120. Gan, C., Mostafid, H., Khan, M. S. & Lewis, D. J. BCG immunotherapy for bladder cancer — the effects of substrain differences. Nat. Rev. Urol. 10, 580–588 (2013).

    CAS  PubMed  Google Scholar 

  121. Boehm, B. E. et al. Efficacy of bacillus Calmette–Guerin strains for treatment of nonmuscle invasive bladder cancer: a systematic review and network meta-analysis. J. Urol. 198, 503–510 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. Witjes, J. A. et al. The efficacy of BCG TICE and BCG Connaught in a cohort of 2,099 patients with T1G3 non-muscle-invasive bladder cancer. Urol. Oncol. 34, 484 (2016).

    PubMed  PubMed Central  Google Scholar 

  123. Secanella-Fandos, S., Noguera-Ortega, E., Olivares, F., Luquin, M. & Julian, E. Killed but metabolically active Mycobacterium bovis bacillus Calmette–Guerin retains the antitumor ability of live bacillus Calmette–Guerin. J. Urol. 191, 1422–1428 (2014).

    CAS  PubMed  Google Scholar 

  124. Liu, Y., Lu, J., Huang, Y. & Ma, L. Clinical spectrum of complications induced by intravesical immunotherapy of bacillus Calmette–Guerin for bladder cancer. J. Oncol. 2019, 6230409 (2019).

    PubMed  PubMed Central  Google Scholar 

  125. Nakagawa, T. et al. Reiter’s syndrome following intravesical bacillus Calmette–Guerin therapy for bladder carcinoma: a report of five cases. Int. Cancer Conf. J. 7, 148–151 (2018).

    PubMed  PubMed Central  Google Scholar 

  126. Arts, R. J. W., Joosten, L. A. B. & Netea, M. G. The potential role of trained immunity in autoimmune and autoinflammatory disorders. Front. Immunol. 9, 298 (2018).

    PubMed  PubMed Central  Google Scholar 

  127. Cabău, G., Crișan, T. O., Klück, V., Popp, R. A. & Joosten, L. A. B. Urate-induced immune programming: consequences for gouty arthritis and hyperuricemia. Immunol. Rev. 294, 92–105 (2020).

    PubMed  Google Scholar 

  128. Arbues, A., Lugo-Villarino, G., Neyrolles, O., Guilhot, C. & Astarie-Dequeker, C. Playing hide-and-seek with host macrophages through the use of mycobacterial cell envelope phthiocerol dimycocerosates and phenolic glycolipids. Front. Cell. Infect. Microbiol. 4, 173 (2014).

    PubMed  PubMed Central  Google Scholar 

  129. Cambier, C. J. et al. Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids. Nature 505, 218–222 (2014).

    CAS  PubMed  Google Scholar 

  130. Kleinnijenhuis, J., Oosting, M., Joosten, L. A., Netea, M. G. & Van Crevel, R. Innate immune recognition of Mycobacterium tuberculosis. Clin. Dev. Immunol. 2011, 405310 (2011).

    PubMed  PubMed Central  Google Scholar 

  131. Chen, J. M., Islam, S. T., Ren, H. & Liu, J. Differential productions of lipid virulence factors among BCG vaccine strains and implications on BCG safety. Vaccine 25, 8114–8122 (2007).

    CAS  PubMed  Google Scholar 

  132. Dinarello, C. A. The IL-1 family of cytokines and receptors in rheumatic diseases. Nature reviews. Rheumatology 15, 612–632 (2019).

    CAS  PubMed  Google Scholar 

  133. Netea, M. G. & Joosten, L. A. B. Trained immunity and local innate immune memory in the lung. Cell 175, 1463–1465 (2018).

    CAS  PubMed  Google Scholar 

  134. Yao, Y. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650 (2018).

    CAS  PubMed  Google Scholar 

  135. Krajewski, W. et al. Does Mantoux test results predict BCG immunotherapy efficiency and severe toxicity in non-muscle invasive bladder cancer. Urol. J. 16, 458–462 (2019).

    PubMed  Google Scholar 

  136. Svatek, R. S., Tangen, C., Delacroix, S., Lowrance, W. & Lerner, S. P. Background and update for S1602 ‘A phase III randomized trial to evaluate the influence of BCG strain differences and T cell priming with intradermal BCG before intravesical therapy for BCG-naive high-grade non-muscle-invasive bladder cancer’. Eur. Urol. Focus. 4, 522–524 (2018).

    PubMed  PubMed Central  Google Scholar 

  137. Novakovic, B. et al. Beta-glucan reverses the epigenetic state of LPS-induced immunological tolerance. Cell 167, 1354–1368 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Netea, M. G., Joosten, L. A. B. & van der Meer, J. W. M. Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer. J. Leukoc. Biol. 102, 1323–1332 (2017).

    CAS  PubMed  Google Scholar 

  139. Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A. & Netea, M. G. Therapeutic targeting of trained immunity. Nat. Rev. Drug Discov. 18, 553–566 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Larsen, E. S., Joensen, U. N., Poulsen, A. M., Goletti, D. & Johansen, I. S. Bacillus Calmette–Guerin immunotherapy for bladder cancer: a review of immunological aspects, clinical effects and BCG infections. Apmis 128, 92–103 (2020).

    PubMed  Google Scholar 

  141. van der Wel, N. et al. M. tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells. Cell 129, 1287–1298 (2007).

    PubMed  Google Scholar 

  142. Shah, G. et al. Loss of bacillus Calmette–Guerin viability adversely affects the direct response of urothelial carcinoma cells to bacillus Calmette–Guerin exposure. J. Urol. 191, 823–829 (2014).

    CAS  PubMed  Google Scholar 

  143. Noguera-Ortega, E. et al. Nonpathogenic Mycobacterium brumae inhibits bladder cancer growth in vitro, ex vivo, and in vivo. Eur. Urol. Focus 2, 67–76 (2016).

    PubMed  Google Scholar 

  144. Packiam, V. T., Pearce, S. M. & Steinberg, G. D. The role of mycobacterial cell wall nucleic acid complex in the treatment of bacillus Calmette–Guerin failures for non-muscle-invasive bladder cancer. Ther. Adv. Urol. 8, 29–37 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Morales, A. et al. Efficacy and safety of MCNA in patients with nonmuscle invasive bladder cancer at high risk for recurrence and progression after failed treatment with bacillus Calmette–Guerin. J. Urol. 193, 1135–1143 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

M.G.N. was supported by a Netherlands Organization for Scientific Research Spinoza Grant (NWO SPI 94-212). L.A.B.J. was supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (P_37_762, MySMIS 103587). S.H.V. is partly supported by a grant from the Netherlands Organization for Scientific Research (NWO Vidi 91717334).

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Author notes

  1. These authors jointly supervised this work: Leo A. B. Joosten, Sita H. Vermeulen

Authors and Affiliations

  1. Department for Health Evidence, Radboud University Medical Center, Radboud Institute for Health Sciences (RIHS), Nijmegen, Netherlands

    Jelmer H. van Puffelen & Sita H. Vermeulen

  2. Department of Internal Medicine, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, Netherlands

    Jelmer H. van Puffelen, Samuel T. Keating, Mihai G. Netea & Leo A. B. Joosten

  3. Department of Urology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, Netherlands

    Egbert Oosterwijk & Antoine G. van der Heijden

  4. Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany

    Mihai G. Netea

  5. Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania

    Leo A. B. Joosten

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  1. Jelmer H. van Puffelen
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  6. Leo A. B. Joosten
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Contributions

All authors made a substantial contribution to discussion of content and reviewed and edited the manuscript before submission. S.H.V., J.H.v.P. and S.T.K. researched data for the article. S.H.V., J.H.v.P., S.T.K. and L.A.B.J. wrote the manuscript.

Corresponding author

Correspondence to Sita H. Vermeulen.

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Competing interests

L.A.B.J. and M.G.N. declare that they are scientific founders of Trained Therapeutics Discovery and are the owners of two patents related to trained immunity. All other authors declare no competing interests.

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Nature Reviews Urology thanks G. Redelman-Sidi, E. Julián and T. Ratliff for their contribution to the peer review of this work.

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van Puffelen, J.H., Keating, S.T., Oosterwijk, E. et al. Trained immunity as a molecular mechanism for BCG immunotherapy in bladder cancer. Nat Rev Urol 17, 513–525 (2020). https://doi.org/10.1038/s41585-020-0346-4

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