Targeting post-translational modifications of Foxp3: a new paradigm for regulatory T cell-specific therapy

Abstract

A healthy immune system is pivotal for the hosts to resist external pathogens and maintain homeostasis; however, the immunosuppressive tumor microenvironment (TME) damages the anti-tumor immunity and promotes tumor progression, invasion, and metastasis. Recently, many studies have found that Foxp3+ regulatory T (Treg) cells are the major immunosuppressive cells that facilitate the formation of TME by promoting the development of various tumor-associated cells and suppressing the activity of effector immune cells. Considering the role of Tregs in tumor progression, it is pivotal to identify new therapeutic drugs to target and deplete Tregs in tumors. Although several studies have developed strategies for targeted deletion of Treg to reduce the TME and support the accumulation of effector T cells in tumors, Treg-targeted therapy systematically affects the Treg population and may lead to the progression of autoimmune diseases. It has been understood that, nevertheless, in disease conditions, Foxp3 undergoes several definite post-translational modifications (PTMs), including acetylation, glycosylation, phosphorylation, ubiquitylation, and methylation. These PTMs not only elevate or mitigate the transcriptional activity of Foxp3 but also affect the stability and immunosuppressive function of Tregs. Various studies have shown that pharmacological targeting of enzymes involved in PTMs can significantly influence the PTMs of Foxp3; thus, it may influence the progression of cancers and/or autoimmune diseases. Overall, this review will help researchers to understand the advances in the immune-suppressive mechanisms of Tregs, the post-translational regulations of Foxp3, and the potential therapeutic targets and strategies to target the Tregs in TME to improve anti-tumor immunity.

Forces at play: exploring factors affecting the cancer metastasis

“…Notably, the conditioned media from 4T1 breast cancer cells induces the expression of chemokine CCL22 in the lung stroma, subsequently elevating Treg levels in the pre-metastatic lung (126). Targeting Treg is an effective anti-cancer therapy as the role of Tregs, particularly the tissue-specific Tregs, in the progression of cancer and cancer metastasis is well studied (127)(128)(129). Accordingly, our previous investigation illustrates the elevated intra-tumoral Treg frequency in HIF1a depleted mice.…”

Reprogramming of regulatory T cells in inflammatory tumor microenvironment: can it become immunotherapy turning point?

“…How PP1 affects Foxp3 expression and Treg function remains a topic of debate ( 9 , 23 , 177 ). According to Hong Nie et al.’s study, during inflammatory circumstances, PP1 dephosphorylated Foxp3 at Ser-418 of FHD, leading to a reduction in Foxp3 expression ( 178 ).…”