Grinberg-Bleyer et al. found that the c-Rel subunit of canonical nuclear factor κB (NF-κB) plays a critical role in the identity and function of activated Tregs. Genetic knockdown of c-Rel decreased expression of Treg activation genes, and reduced melanoma growth in mice by impairing activated Treg-mediated immunosuppression of CD8+ T cell responses. Use of the FDA-approved drug pentoxifylline to knock down c-Rel showed antitumor efficacy in vivo, especially when combined with anti-PD-1.
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 kappaB (NF-kappaB) subunits, p65 and c-Rel, in Treg identity and function. In this report, we show that NF-kappaB 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-kappaB c-Rel as a viable therapeutic approach for enhancing checkpoint-targeting immunotherapy protocols.