Extensive research in the past decades has highlighted the tight link between immunity and cancer, leading to the development of immunotherapies that have revolutionized cancer care. However, only a fraction of patients display durable responses to these treatments, and a deeper understanding of the cellular and mechanisms orchestrating immune responses to tumors is mandatory for the discovery of novel therapeutic targets. Among the most scrutinized immune cells, Forkhead Box Protein P3 (Foxp3)+ Regulatory T cells (Treg cells) are central inhibitors of protective anti-tumor immunity. These tumor-promoting functions render Treg cells attractive immunotherapy targets, and multiple strategies are being developed to inhibit their recruitment, survival, and function in the tumor microenvironment. In this context, it is critical to decipher the complex and multi-layered molecular mechanisms that shape and stabilize the Treg cell transcriptome. Here, we provide a global view of the transcription factors, and their upstream signaling pathways, involved in the programming of Treg cell homeostasis and functions in cancer. We also evaluate the feasibility and safety of novel therapeutic approaches aiming at targeting specific transcriptional regulators.

NF-kappaB (NF-κB) is a family of transcription factors with pleiotropic functions in immune responses. The alternative NF-κB pathway that leads to the activation of RelB and NF-κB2, was previously associated with the activation and function of T cells, though the exact contribution of these NF-κB subunits remains unclear. Here, using mice carrying conditional ablation of RelB in T cells, we evaluated its role in the development of conventional CD4+ T (Tconv) cells and their function in autoimmune diseases. RelB was largely dispensable for Tconv cell homeostasis, activation and proliferation, and for their polarization toward different flavors of Thelper cells in vitro. Moreover, ablation of RelB had no impact on the capacity of Tconv cells to induce autoimmune colitis. Conversely, clinical severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS) was significantly reduced in mice with RelB-deficient T cells. This was associated with impaired expression of granulocyte–macrophage colony-stimulating factor (GM-CSF) specifically in the central nervous system. Our data reveal a discrete role for RelB in the pathogenic function of Tconv cells during EAE, and highlight this transcription factor as a putative therapeutic target in MS.

Whereas CD4+ effector T cells (Teff cells) are critical to limit tumor progression, uncontrolled Teff cell activation can also lead to autoimmunity; however the molecular basis of these functions are elusive. Here we investigated the selective functions of distinct NF-kappaB transcription factors in the function of Teff cells. Using mice carrying conditional ablation of the canonical NF-kB subunits RelA and c-Rel, in Teff cells, we found that RelA, rather than c-Rel, shaped the transcriptome of Teff cells in the steady-state and their ability to polarize toward the TH17 lineage, by directly binding to genes encoding cytokines and other transcription factors. Similar conclusions could be reached using CRISPR/Cas9-edited primary human Teff cells. Consistently, RelA – but not c-Rel-deficient mice were fully protected against neuro-inflammation in a murine model of multiple sclerosis. Mechanistically, TH17 priming and in situ reactivation, were impaired in RelA-deficient mice. Next, we investigated the roles of NF-kB in cancer immunity. Strikingly, Teff-restricted ablation of c-Rel, but not RelA, impaired their accumulation and function in the microenvironment of melanoma, resulting in enhanced cancer burden. In addition, c-Rel-deficiency abrogated the therapeutic effect of PD-1-blockade. Accordingly, in melanoma patients, the expression of c-Rel-dependent genes was associated with prolonged survival and better response to immunotherapy. Together, our data highlight novel, context-dependent, regulators of Teff cell function. We propose a division of labor between the different subunits of the NF-kB pathway, paving the way to subunit-targeted immunotherapies in autoimmunity and cancer.