Cancers use a wide variety of mechanisms to dampen tumor immune response. Among them, CD4+Foxp3+ regulatory T cells (Tregs) are largely described to inhibit the function of effector cells. In several murine models of cancer, Treg depletion suppresses tumor growth. Interestingly, it has been proposed that anti-CTLA-4 therapies exert their anti-tumor effects by targeting Tregs. Therefore, precisely understanding the mechanisms governing Treg homeostasis may be a valuable strategy to enhance immune responses against cancer. We and other have previously shown that transcription factor NF-κB plays a major role in Treg development; we are now analyzing the role of different NF-κB subunits in Tregs by using conditional knock-out mice.
We found that both p65 (RelA) and c-Rel subunits of NF-κB in Tregs, were required for both development of thymic Treg progenitors and subsequent differentiation into Foxp3-expressing mature Tregs. Ablation of NF-κB also prevented in vitro differentiation of inducible Tregs. Furthermore, specific deletion of either p65 or c-Rel subunits in natural Tregs using FoxP3-cre led to the development of a lethal autoimmune syndrome by 8 to 15 weeks of age. Ablation of both subunits further shortened the lifespan of animals to around 3 weeks of age. This was associated with profound changes in the molecular signature of NF-κB deficient Tregs, which down-regulated Treg-associated genes while acquiring an effector-like phenotype. Also, tamoxifen-induced acute deletion of NF-κB in mature Tregs reduced their survival and expression of Treg-associated markers. These data highlight a crucial role for NF-κB in maintaining Treg identity in vivo.
We next explored the role of NF-κB in Treg homeostasis during tumor growth. Strikingly, melanoma growth was drastically reduced in mice lacking c-Rel, but not p65, in Tregs. This was associated with an increased polyclonal and antigen-specific effector T cell activation. Besides, CD8 T cell depletion abolished the protection against tumor growth. We are now proceeding to test the effect of specific c-Rel inhibitors on tumor growth. We believe our work reveals a central molecular mechanism in the maintenance of Treg identity and thus highlights novel therapeutic target for the treatment of cancer.
Citation Format: Yenkel Grinberg-Bleyer, Hyunju Ho, Roland Schmid, Ulf Klein, Sankar Ghosh. The canonical NF-κB pathway is crucial for Treg homeostasis during the antitumor response. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B060.