Trained Immunity-Promoting Nanobiologic Therapy Suppresses Tumor Growth and Potentiates Checkpoint Inhibition
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Trained immunity, a functional state of myeloid cells, has been proposed as a compelling immune-oncological target. Its efficient induction requires direct engagement of myeloid progenitors in the bone marrow. For this purpose, we developed a bone marrow-avid nanobiologic platform designed specifically to induce trained immunity. We established the potent anti-tumor capabilities of our lead candidate MTP 10-HDL in a B16F10 mouse melanoma model. These anti-tumor effects result from trained immunity-induced myelopoiesis caused by epigenetic rewiring of multipotent progenitors in the bone marrow, which overcomes the immunosuppressive tumor microenvironment. Furthermore, MTP 10-HDL nanotherapy potentiates checkpoint inhibition in this melanoma model refractory to anti-PD-1 and anti-CTLA-4 therapy. Finally, we determined MTP 10-HDL's favorable biodistribution and safety profile in non-human primates. In conclusion, we show that rationally designed nanobiologics can promote trained immunity and elicit a durable anti-tumor response either as a monotherapy or in combination with checkpoint inhibitor drugs.
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NOD2 stimulation by MDP and its analogs can alter host immunity through multiple pathways, including macrophage activation for tumor clearance, epigenetic reprogramming of monocytes, generation of conventional type 1 dendritic cells, and dendritic cell priming for cross-presentation to CD8+ T cells.
“our findings corroborate a wealth of emerging evidence that NOD2 stimulation by MDP and its analogs can alter host immunity through multiple pathways including the direct activation of macrophages for tumor cell clearance (39), epigenetic reprogramming of monocytes (40, 41), generation of conventional type 1 dendritic cells (42), and priming of dendritic cells for cross-presentation to CD8+ T cell”
From <i>Enterococcus</i> peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy (2021) · cites this paper as [41]
A bone marrow homing nanoparticle therapeutically containing immunostimulatory muramyl tripeptide shows anti-tumor effects by epigenetic reprograming of multipotent progenitor cells in the bone marrow, overcoming the immunosuppressive TME.
“For this, myeloid progenitor differentiation has been manipulated via a bone marrow homing nanoparticle therapeutically containing the immunostimulatory muramyl tripeptide. This peptide shows anti‐tumor effects by epigenetic reprograming of the multipotent progenitor cells in the bone marrow, which overcomes the immunosuppressive TME [55].”
From Tumor microenvironment signaling and therapeutics in cancer progression (2023) · cites this paper as [55]
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- Authors
- Priem, B., van Leent, M. M. T., Teunissen, A. J. P., Sofias, A. M., Mourits, V. P., Willemsen, L., Klein, E. D., Oosterwijk, R. S., Meerwaldt, A. E., Munitz, J., Prévot, G., Vera Verschuur, A., Nauta, S. A., van Leeuwen, E. M., Fisher, E. L., de Jong, K. A. M., Zhao, Y., Toner, Y. C., Soultanidis, G., Calcagno, C., Bomans, P. H. H., Friedrich, H., Sommerdijk, N., Reiner, T., Duivenvoorden, R., Zupančič, E., Di Martino, J. S., Kluza, E., Rashidian, M., Ploegh, H. L., Dijkhuizen, R. M., Hak, S., Pérez-Medina, C., Bravo-Cordero, J. J., de Winther, M. P. J., Joosten, L. A. B., van Elsas, A., Fayad, Z. A., Rialdi, A., Torre, D., Guccione, E., Ochando, J., Netea, M. G., Griffioen, A. W., & Mulder, W. J. M.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Icahn School of Medicine at Mount Sinai (US)
- Norwegian University of Science and Technology (NO)
- Radboud University Nijmegen (NL)
- Amsterdam University Medical Centers (NL)
- Utrecht University (NL)
- Eindhoven University of Technology (NL)
- Radboud University Medical Center (NL)
- Memorial Sloan Kettering Cancer Center (US)
- Harvard University (US)
- Instituto de Salud Carlos III (ES)
- University of Bonn (DE)
- Corresponding author
- Mulder, Willem J.M.
- ORCID
- Priem, Bram
- Teunissen, Abraham J.P.
- Sofias, Alexandros Marios
- Mourits, Vera P.
- Willemsen, Lisa
- Klein, Emma D.
- Meerwaldt, Anu E.
- Munitz, Jazz
- Prévot, Geoffrey
- Nauta, Sheqouia A.
- Fisher, Elizabeth L.
- Zhao, Yiming
- Toner, Yohana C.
- Soultanidis, Georgios
- Calcagno, Claudia
- Friedrich, Heiner
- Sommerdijk, Nico
- Reiner, Thomas
- Duivenvoorden, Raphaël
- Kluza, Ewelina
- Rashidian, Mohammad
- Ploegh, Hidde L.
- Dijkhuizen, Rick M.
- Hak, Sjoerd
- Joosten, Leo A.B.
- Fayad, Zahi A.
- Rialdi, Alexander
- Torre, Denis
- Guccione, Ernesto
- Ochando, Jordi
- Netea, Mihai G.
- Griffioen, Arjan W.
- Mulder, Willem J.M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 183
- Issue
- 3
- Pages
- 786-801.e19
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC8074872
- OpenAlex
- W3097770322
- Cited by
- 222
- References
- 62
- Citations by year
- 2026: 36 · 2025: 53 · 2024: 33 · 2023: 31 · 2022: 35 · 2021: 31 · 2020: 3
- FWCI
- 8.76
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- TU/e Research Portal (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- TU/e Research Portal (submittedVersion)
- Funders
- National Institutes of Health (R01 AI139623, R01 HL143814, R01 HL144072, P01 HL131478, R01 CA220234)
- National Cancer Institute (K22CA196750, P30-CA19652)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- U.S. Army Materiel Command
- American Cancer Society (1K22CA226040-01)
- ZonMw (R01 AI139623, P01HL131478, R01 HL143814)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- trained immunity, tumor growth inhibition, immune checkpoint inhibitors, combination immunotherapy, antitumor immunity, nanoparticle biodistribution, non-human primate safety
- MeSH terms
- Immune Checkpoint Inhibitors, Acetylmuramyl-Alanyl-Isoglutamine, Animals, Behavior, Animal, Bone Marrow Cells, Cholesterol, Female, Hematopoietic Stem Cells, Immunity, Immunotherapy, Lipoproteins, HDL, Melanoma, Experimental, Mice, Inbred C57BL, Primates, Tissue Distribution, Nanotechnology, Cell Proliferation, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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