p300 Blockade Promotes Antitumor Immunity

The immune-suppressive functions of regulatory T (Treg) cells prevent autoimmunity but also inhibit effective antitumor immune responses. Depletion of Treg cells has been proposed as a potential strategy for cancer immunotherapy but often results in the induction of autoimmunity, emphasizing the need for alternative approaches to target Treg cells. Recent studies have shown that acetylation enhances the expression of forkhead box P3 (FOXP3), a Treg-cell–specific transcription factor, prompting Liu and colleagues to investigate whether inhibition of the histone acetyltransferase p300 (encoded by Ep300) modulates Treg-cell function. Genetic deletion of Ep300 specifically in FOXP3⁺ Treg cells impaired Treg-cell suppressive function in adoptive transfer experiments and increased Treg-cell apoptosis in response to immune activation. This effect occurred without inducing severe autoimmunity, indicating that p300 is required for Treg-cell survival and function. In addition, Ep300 ablation decreased Treg-cell proliferation and intratumoral infiltration and increased the accumulation of CD8⁺ effector T cells, leading to decreased tumor growth in mice, and suggesting that p300 blockade enhances antitumor immunity. In support of this idea, a small-molecule p300 inhibitor reduced FOXP3 acetylation and expression in Treg cells, promoted Treg-cell death, and compromised Treg-cell suppressive function and induction of peripheral Treg cells in vitro. Treatment with the p300 inhibitor did not affect conventional T-cell function but prevented Treg-cell–dependent allograft survival in transplant experiments. Importantly, pharmacologic blockade of p300 suppressed the growth of established tumors in immunocompetent but not immunodeficient mice; this antitumor effect was accompanied by increased infiltration of mononuclear cells and CD8⁺ effector T cells and reduced intratumoral FOXP3 expression, similar to the effects of conditional Ep300 deletion. These findings identify p300 as a critical regulator of Treg-cell homeostasis and suggest targeted inhibition of p300 as a new therapeutic strategy to improve antitumor immune responses.

Liu Y, Wang L, Predina J, Han R, Beier UH, Wang LC, et al. Inhibition of p300 impairs Foxp3⁺ T regulatory cell function and promotes antitumor immunity. Nat Med 2013 Aug 18 [Epub ahead of print].