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OPINION

Therapeutic targeting of trained immunity

Abstract

Immunotherapy is revolutionizing the treatment of diseases in which dysregulated immune responses have an important role. However, most of the immunotherapy strategies currently being developed engage the adaptive immune system. In the past decade, both myeloid (monocytes, macrophages and dendritic cells) and lymphoid (natural killer cells and innate lymphoid cells) cell populations of the innate immune system have been shown to display long-term changes in their functional programme through metabolic and epigenetic programming. Such reprogramming causes these cells to be either hyperresponsive or hyporesponsive, resulting in a changed immune response to secondary stimuli. This de facto innate immune memory, which has been termed ‘trained immunity’, provides a powerful ‘targeting framework’ to regulate the delicate balance of immune homeostasis, priming, training and tolerance. In this Opinion article, we set out our vision of how to target innate immune cells and regulate trained immunity to achieve long-term therapeutic benefits in a range of immune-related diseases. These include conditions characterized by excessive trained immunity, such as inflammatory and autoimmune disorders, allergies and cardiovascular disease and conditions driven by defective trained immunity, such as cancer and certain infections.

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Fig. 1: Excessive and defective trained immunity in disease.
Fig. 2: Processes that control trained immunity, at the epigenetic, cellular and systems level.
Fig. 3: Trained-immunity-regulating pathways.
Fig. 4: Molecular structures that induce or inhibit trained immunity.
Fig. 5: Regulating trained immunity with nanotechnology.
Fig. 6: Combining therapeutically induced and inhibited trained immunity with adaptive immunity-regulating agents.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) grants R01 CA220234, R01 HL144072, P01 HL131478, and Netherlands Organization for Scientific Research (NWO) grant ZonMW Vici 91818622 (all to W.J.M.M.), as well as NIH grants R01 HL143814 and P01HL131478 (both to Z.A.F.). J.O. is supported by R01 AI139623, as well as SAF2013-48834-R and SAF2016-80031-R grants from the Spanish Government. L.A.B.J. is supported by a Competitiveness Operational Programme grant of the Romanian Ministry of European Funds (HINT, P_37_762). M.G.N. is supported by a European Research Council (ERC) Consolidator Grant (#310372) and an NWO Spinoza Prize. The authors thank K. Joyes for editing the manuscript.

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W.J.M.M. and M.G.N. wrote the manuscript. All authors researched data for the article, provided substantial contribution to discussion of content and reviewed and edited the manuscript before submission.

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Correspondence to Willem J. M. Mulder or Mihai G. Netea.

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Mulder, W.J.M., Ochando, J., Joosten, L.A.B. et al. Therapeutic targeting of trained immunity. Nat Rev Drug Discov 18, 553–566 (2019). https://doi.org/10.1038/s41573-019-0025-4

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