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

Yujie Liu, Liqing Wang, Jarrod Predina, Rongxiang Han, Ulf H. Beier, Liang Chuan S. Wang, Veena Kapoor, Tricia R. Bhatti, Tatiana Akimova, Sunil Singhal, Paul K. Brindle, Philip A. Cole, Steven M. Albelda, Wayne W. Hancock

Research output: Contribution to journalArticle

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 tumors. 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+ T reg 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 proteins. We now report that conditional deletion or pharmacologic inhibition of one HAT, p300 (also known as Ep300 or KAT3B), in Foxp3+ T reg cells increased T cell receptor-induced apoptosis in T reg 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.

Original languageEnglish (US)
Pages (from-to)1173-1177
Number of pages5
JournalNature medicine
Volume19
Issue number9
DOIs
StatePublished - Sep 1 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Liu, Y., Wang, L., Predina, J., Han, R., Beier, U. H., Wang, L. C. S., Kapoor, V., Bhatti, T. R., Akimova, T., Singhal, S., Brindle, P. K., Cole, P. A., Albelda, S. M., & Hancock, W. W. (2013). Inhibition of p300 impairs Foxp3+ T regulatory cell function and promotes antitumor immunity. Nature medicine, 19(9), 1173-1177. https://doi.org/10.1038/nm.3286