Inhibition of p300 impairs Foxp3(+) T-regulatory cell function and promotes anti-tumor immunity

Foxp3(+) T-regulatory (T(reg)) cells maintain immune homeostasis and limit autoimmunity, but can also curtail host immune responses to various types of tumors(1,2). Foxp3(+) T(regs) 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(+) T(reg) 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 proteins(3,4). We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (Ep300, KAT3B), in Foxp3(+) T(regs), increased TCR-induced apoptosis in T(regs), impaired T(reg) suppressive function and peripheral T(reg) induction, and limited tumor growth in immunocompetent, but not in immunodeficient, hosts. Our data thereby demonstrate that p300 is important for Foxp3(+) T(reg) function and homeostasis in vivo and in vitro, and identify novel mechanisms by which appropriate small molecule inhibitors can diminish T(reg) function without overtly impairing T-effector (T(eff)) cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.