Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity

Abstract

Foxp3+ T-regulatory (Treg) cells maintain immune homeostasis and limit autoimmunity, but can also curtail host immune responses to various types of tumors1,2. Foxp3+ Tregs are therefore considered promising targets to enhance anti-tumor immunity, and efforts are underway to develop approaches for their therapeutic modulation. However, while studies showing that Foxp3+ Treg depletion experimentally can enhance anti-tumor responses provide proof-of-principle, they lack clear translational potential and have various shortcomings. Histone/protein acetyltransferases (HATs) promote chromatin accessibility, gene transcription and the function of multiple transcription factors and non-histone proteins3,4. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (Ep300, KAT3B), in Foxp3+ Tregs, increased TCR-induced apoptosis in Tregs, impaired Treg suppressive function and peripheral Treg induction, and limited tumor growth in immunocompetent, but not in immunodeficient, hosts. Our data thereby demonstrate that p300 is important for Foxp3+ Treg function and homeostasis in vivo and in vitro, and identify novel mechanisms by which appropriate small molecule inhibitors can diminish Treg function without overtly impairing T-effector (Teff) cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.

FOXP3+ regulatory T cell development and function require histone/protein deacetylase 3

“…Thus, pan-histone/protein deacetylase inhibitors (pan-HDACi) increase FOXP3 acetylation and DNA binding, enhance Treg production and suppressive activity, and have beneficial effects in the prevention and treatment of autoimmune disease and transplant rejection (10). Conversely, targeting of the histone acetyltransferase p300 can impair FOXP3 acetylation and Treg function while preserving T effector cell (Teff) responses and thereby promote immune responses in tumor-bearing hosts (11).…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…In cancer, such targeting strategies could have dual effects by directly impeding the cancer cells and by modulating the antitumour immune response 189 . Inhibiting the activity of HATs globally has selective effects on T Reg cell plasticity, driving T Reg cells to lose FOXP3 expression and gain IL-17 production, and probably accounts for the improved antitumour immune responses observed with this approach 141,190 . Alternatively, blocking the interactions of bromodomain-containing proteins with acetylated histones through the use of BET inhibitors (bromo domain and extraterminal inhibitors) reduces the severity of autoimmune disease in mouse models of multiple sclerosis and type 1 diabetes by broadly skewing immunity towards regulatory phenotypes 191,192 .…”

FOXP3+ regulatory T cells and their functional regulation

“…57 In vivo data also confirmed that a p300 specific inhibitor could decrease FOXP3 acetylation and Treg cell activity in mice. 75 On the other hand, two lysine deacetylases, HDAC9 and SIRT1, can associate to FOXP3, and downregulates FOXP3 acetylation level and Treg activity, where knockdown of HDAC9 or SIRT1 has been shown to enhance Treg suppressive function in vitro. 76,77 Proteins with Lysine-48 (K48)-linked poly-ubiquitination may undergo proteasome-mediated degradation.…”

“…A PIM1-specific inhibitor could potentially be used to enhance the immunosuppressive activity of Treg cells through downregulating the phosphorylation of FOXP3-Ser422 during ex vivo preparation of Treg cells, 54 while PP1-specific inhibitor may work reversely and weaken the immunosuppressive activity of Treg cells; 60 STUB1-specific inhibitors, may stabilize Treg cells through preventing FOXP3 ubiquitination and degradation, whereas USP7-specific inhibitor treated Treg cells may lose their stability through promoting the process; 31,55 SIRT1/HDAC9 inhibitors would enhance the activity of Treg cells through promoting FOXP3 acetylation and facilitating its stability or activity upregulation, while P300/TIP60 inhibitors may abolish the process and promote FOXP3 degradation mediated by FOXP3 ubiquitination. 53,57,75,76 Along with the accumulation of our knowledge on the molecular mechanism of Treg immunosuppressive activity, we expect that in the next few years, increasingly safe and effective compounds, which could aid the ex vivo expansion of Treg cells by helping to maintain their stable function in vivo, will be identified and advance into clinical trials for the treatment of autoimmune diseases and other inflammatory diseases.…”