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

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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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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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.

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Correspondence to Sita H. Vermeulen.

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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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