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

• Published in: Cell 2017-09, Vol.170 (6), p.1096-1108.e13
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; cancer; Disease Models, Animal; Female; immunotherapy; Immunotherapy - methods; Male; Melanoma - immunology; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; NF-κB; Proto-Oncogene Proteins c-rel - antagonists & inhibitors; regulatory T cells; T-Lymphocytes, Regulatory - immunology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.08.004

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. [Display omitted] •NF-κB c-Rel regulates the transcriptional landscape of activated Tregs•c-Rel activity in Tregs restricts anti-tumor responses•Chemical c-Rel inhibition reduces melanoma growth and potentiates anti-PD-1 therapy NF-κB c-Rel is critical for the function of activated Tregs and serves as a target to reduce Treg function in the tumor microenvironment without compromising systemic tolerance or causing autoimmunity.