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

Abstract

Forkhead box P3 (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+ Treg cells are therefore considered promising targets to enhance antitumor immunity, and approaches for their therapeutic modulation are being developed. However, although studies showing that experimentally depleting Foxp3+ Treg cells can enhance antitumor responses provide proof of principle, these studies 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 nonhistone proteins3,4. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3+ Treg cells increased T cell receptor–induced apoptosis in Treg cells, impaired Treg cell suppressive function and peripheral Treg cell induction, and limited tumor growth in immunocompetent but not in immunodeficient mice. Our data thereby demonstrate that p300 is important for Foxp3+ Treg cell function and homeostasis in vivo and in vitro, and identify mechanisms by which appropriate small-molecule inhibitors can diminish Treg cell function without overtly impairing T effector cell responses or inducing autoimmunity. Collectively, these data suggest a new approach for cancer immunotherapy.

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Figure 1: Effects of conditional deletion of Ep300 in Foxp3+ Treg cells.
Figure 2: Treg cell–specific deletion of Ep300 enhances antitumor immunity.
Figure 3: Use of p300i decreased Foxp3 acetylation and Treg function.
Figure 4: p300i therapy impaired tumor growth in immunocompetent mice.

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Acknowledgements

We thank E. Verdin (Gladstone Institute of Virology and Immunology, University of California–San Francisco) for antibody to acetylated Foxp3; X.-J. Yang (Department of Medicine, McGill University) for p300 expression vector; Y. Paterson (Department of Microbiology, University of Pennsylvania) for TC1 cell lines; and D. Nelson (Department of Medicine, University of Western Australia) for the AE17.OVA mesothelioma cell line. This work was supported by grants from the US National Institutes of Health (K08AI095353 to U.H.B. and P01AI073489 and 1R01CA158941 to W.W.H.).

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Y.L. and L.W. performed most studies, analyzed data and edited the manuscript. Y.L. wrote the manuscript. J.P., L.-C.S.W., V.K., S.S. and S.M.A. performed tumor studies and analyzed tumor data. R.H. undertook mouse breeding and performed histology. U.H.B. analyzed microarray data, analyzed data and edited the manuscript. T.R.B. performed histology. T.A. performed autoantibody screening, analyzed data and edited the manuscript. P.K.B. and P.A.C. provided unique mice and reagents, respectively, and analyzed data. W.W.H. designed and directed this study, analyzed data and edited the manuscript.

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Correspondence to Wayne W Hancock.

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The authors declare no competing financial interests.

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Liu, Y., Wang, L., Predina, J. et al. Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity. Nat Med 19, 1173–1177 (2013). https://doi.org/10.1038/nm.3286

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