Cited by 297T-cell and B-cell ImmunologyCancer Immunotherapy and BiomarkersTGF-β signaling in diseases

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NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer

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Grinberg-Bleyer, Yenkel, Oh, Hyunju, Desrichard, Alexis, Bhatt, Dev M., Caron, Rachel, Chan, Timothy A., Schmid, Roland M., Klein, Ulf, Hayden, Matthew S., Ghosh, Sankar·2017·Cell

DOI 10.1016/j.cell.2017.08.004PMC PMC5633372

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Abstract

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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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: Desrichard, Alexis
Bhatt, Dev M.
Caron, Rachel
Chan, Timothy A.
Schmid, Roland M.
Klein, Ulf
Hayden, Matthew S.
Ghosh, Sankar
Venue: Cell
Publisher: Elsevier BV
Published: 2017-09
Volume: 170
Issue: 6
Pages: 1096-1108.e13
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2017.08.004
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: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 372 d)
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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NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer

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