Transcriptional Control of Regulatory T Cells in Cancer: Toward Therapeutic Targeting?

SIMPLE SUMMARY: Cancer outcomes are often indexed to the quality of the immune response to the tumor. Among immune cells, Foxp3(+) regulatory T cells (Treg cells) are potent inhibitors of cancer immunity, and their presence within solid tumors is generally associated with a poor prognosis. Thus, understanding how Treg cell identity is controlled, is of utmost importance for the development of novel anti-cancer therapies. In this review, we summarize the current knowledge on the different intracellular pathways involved in the programming of Treg cell homeostasis and functions in cancer. We also highlight the therapeutic approaches aiming at targeting these regulators to enhance anti-tumor immunity. ABSTRACT: 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.