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Cell. 2017 Sep 7;170(6):1096-1108.e13. doi: 10.1016/j.cell.2017.08.004.

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

Author information

1
Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
2
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
II Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität Munich, Munich, Germany.
4
Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center and Department of Pathology & Cell Biology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA.
5
Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA; Section of Dermatology, Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
6
Department of Microbiology & Immunology, College of Physicians & Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: sg2715@cumc.columbia.edu.

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.

KEYWORDS:

NF-κB; cancer; immunotherapy; regulatory T cells

PMID:
28886380
PMCID:
PMC5633372
DOI:
10.1016/j.cell.2017.08.004
[Indexed for MEDLINE]
Free PMC Article

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