Development of NR0B2 as a therapeutic target for the re-education of tumor associated myeloid cells
Open accessAbstract
Immune checkpoint blockade (ICB) has had limited utility in several solid tumors such as breast cancer, a major cause of cancer-related mortality in women. Therefore, there is considerable interest in alternate strategies to promote an anti-cancer immune response. A paper co-published in this issue describes how NR0B2, a protein involved in cholesterol homeostasis, functions within myeloid immune cells to modulate the inflammasome and reduce the expansion of immune-suppressive regulatory T cells (Treg). Here, we develop NR0B2 as a potential therapeutic target. NR0B2 in tumors is associated with improved survival for several cancer types including breast. Importantly, NR0B2 expression is also prognostic of ICB success. Within breast tumors, NR0B2 expression is inversely associated with FOXP3, a marker of Tregs. While a described agonist (DSHN) had some efficacy, it required high doses and long treatment times. Therefore, we designed and screened several derivatives. A methyl ester derivative (DSHN-OMe) emerged as superior in terms of (1) cellular uptake, (2) ability to regulate expected expression of genes, (3) suppression of Treg expansion using in vitro co-culture systems, and (4) efficacy against the growth of primary and metastatic tumors. This work identifies NR0B2 as a target to re-educate myeloid immune cells and a novel ligand with significant anti-tumor efficacy in preclinical models.
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An NR0B2 agonist has significant anti-tumor activity in murine models.
“A recently developed agonist of NR0B2 was demonstrated to have significant anti-tumor activity in murine models (26).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [26]
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RetractedCholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells
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- Authors
- Vidana Gamage, H. E., Albright, S. T., Smith, A. J., Farmer, R., Shahoei, S. H., Wang, Y., Fink, E. C., Jacquin, E., Weisser, E., Bautista, R. O., Henn, M. A., Schane, C. P., Nelczyk, A. T., Ma, L., Das Gupta, A., Bendre, S. V., Nguyen, T., Tiwari, S., Krawczynska, N., He, S., Tjoanda, E., Chen, H., Sverdlov, M., Gann, P. H., Boidot, R., Vegran, F., Fanning, S. W., Apetoh, L., Hergenrother, P. J., & Nelson, E. R.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Loyola University Chicago (US)
- University of Illinois Chicago (US)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Nelson, Erik R.
- ORCID
- Vidana Gamage, Hashni Epa
- Smith, Amanda J.
- Shahoei, Sayyed Hamed
- Wang, Yu
- Fink, Emma C.
- Jacquin, Elise
- Weisser, Erin
- Schane, Claire P.
- Nelczyk, Adam T.
- Ma, Liqian
- Das Gupta, Anasuya
- Bendre, Shruti V.
- Krawczynska, Natalia
- He, Sisi
- Chen, Hong
- Sverdlov, Maria
- Gann, Peter H.
- Boidot, Romain
- Fanning, Sean W.
- Hergenrother, Paul J.
- Nelson, Erik R.
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2024-08
- Volume
- 597
- Pages
- 217086
- ISSN
- 0304-3835 (ISSN-L)
- PMC
- PMC11890212
- OpenAlex
- W4400139433
- Cited by
- 13
- References
- 44
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 1
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cancer Letters (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- Funders
- U.S. Department of Defense (W81XWH, BC200206/W81XWH-20-BCRP-EOHS)
- Memorial Sloan-Kettering Cancer Center
- Agence Nationale de la Recherche (ANR-11-LABX-0021)
- Fondation pour la Recherche Médicale (ARF20170938687)
- National Institutes of Health (W81XWH)
- University of Illinois at Urbana-Champaign
- National Cancer Institute (R01CA234025)
- National Institute of General Medical Sciences (T32GM136629)
- National Institute of Environmental Health Sciences (T32ES007326)
- National Institute of Biomedical Imaging and Bioengineering (T32EB019944)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- NR0B2, cholesterol homeostasis, tumor-associated myeloid cells, regulatory T cells, Foxp3, inflammasome, immune checkpoint blockade, breast cancer, therapeutic target, antitumor immunity, tumor microenvironment
- MeSH terms
- Immune Checkpoint Inhibitors, Animals, Breast Neoplasms, Female, Humans, Myeloid Cells, Cell Line, Tumor, T-Lymphocytes, Regulatory, Mice, Tumor Microenvironment
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