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NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer
Open accessAbstract
Regulatory T cells (Tregs) play a pivotal role in the inhibition of anti-tumor immune responses. Understanding the mechanisms governing Treg homeostasis may therefore be important for development of effective tumor immunotherapy. We have recently demonstrated a key role for the canonical nuclear factor κB (NF-κB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-κB c-Rel ablation specifically impairs the generation and maintenance of the activated Treg (aTreg) subset, which is known to be enriched at sites of tumors. Using mouse models, we demonstrate that melanoma growth is drastically reduced in mice lacking c-Rel, but not p65, in Tregs. Moreover, chemical inhibition of c-Rel function delayed melanoma growth by impairing aTreg-mediated immunosuppression and potentiated the effects of anti-PD-1 immunotherapy. Our studies therefore establish inhibition of NF-κB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.
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“Among the RECs, the aTregs subset displayed elevated activity of the regulons corresponding to Foxp3, nuclear factor κB (NF-κB) TF family (Nfkb1, Nfkb2, Rel, and Relb), Irf4, and Maf, which were previously associated with activation phenotype of Tregs [Fig. 5B; (46, 47)].”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [47]
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Self-citation
Metadata
- Authors
- Grinberg-Bleyer, Y., Oh, H., Desrichard, A., Bhatt, D. M., Caron, R., Chan, T. A., Schmid, R. M., Klein, U., Hayden, M. S., & Ghosh, S.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Columbia University (US)
- TUM Klinikum (DE)
- Herbert Irving Comprehensive Cancer Center (US)
- Dartmouth–Hitchcock Medical Center (US)
- Columbia University Irving Medical Center (US)
- Corresponding author
- Ghosh, Sankar
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 170
- Issue
- 6
- Pages
- 1096-1108.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5633372
- OpenAlex
- W2739636520
- Cited by
- 297
- References
- 56
- Citations by year
- 2026: 13 · 2025: 25 · 2024: 35 · 2023: 29 · 2022: 34 · 2021: 35 · 2020: 49 · 2019: 41 · 2018: 30 · 2017: 6
- FWCI
- 15.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- Cancer Research Institute
- NIH (R01-AI068977)
- Herbert Irving Cancer Center at Columbia University
- Columbia University
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- c-Rel, NF-κB, regulatory T cells, tumor immune checkpoint, melanoma, anti-PD-1 therapy, immunosuppression, cancer immunotherapy, NF-κB p65
- MeSH terms
- Animals, Disease Models, Animal, Female, Immunotherapy, Male, Melanoma, Mice, Inbred C57BL, NF-kappa B, Mice, Knockout, Proto-Oncogene Proteins c-rel, T-Lymphocytes, Regulatory, Mice
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