SEMINAR

T-regulatory cells (Treg) play a pivotal role in the inhibition of anti-tumor immune responses. We have therefore explored the importance of NF-kB in tumor immune tolerance using mouse models for melanoma. We observed that melanoma growth is drastically reduced in mice lacking the NF-kB subunit c-Rel, but not p65, specifically in Treg cells. Moreover, chemical inhibition of c-Rel delayed melanoma growth and potentiated anti-PD-1 immunotherapy by impairing the Treg transcriptional program. As c-Rel inhibition has a mild effect on in vivo CD8+ T-cell responses, our studies establish inhibition of NF-kB c-Rel as a viable therapeutic approach for enhancing checkpoint targeting immunotherapy protocols. We are therefore also attempting to identify more specific inhibitors of c-Rel, and we will discuss those approaches.