Ubiquitin-specific Protease-7 Inhibition Impairs Tip60-dependent Foxp3 + T-regulatory Cell Function and Promotes Antitumor Immunity

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• 作者：Liqing Wang^a ; Suresh Kumar^b ; Satinder Dahiya^a ; Feng Wang^b ; Jian Wu^b ; Kheng Newick^c ; Rongxiang Han^a ; Arabinda Samanta^a ; Ulf H. Beier^d ; Tatiana Akimova^a ; Tricia R. Bhatti^a ; Benjamin Nicholson^b ; ¹ ; Mathew P. Kodrasov^b ; Saket Agarwal^b ; David E. Sterner^b ; Wei Gu^e ; Joseph Weinstock^b ; Tauseef R. Butt^b ; Steven M. Albelda^c ; Wayne W. Hancock^a ; ^{whancock@mail.med.upenn.edu}
• 关键词：Immuno-oncology ; Anti-tumor immunity ; T-regulatory cells ; Deubiquitination
• 刊名：EBioMedicine
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：13
• 期：Complete
• 页码：99-112
• 全文大小：2726 K
• 卷排序：13

文摘

Conditional deletion of Usp7 in Foxp3 + Treg cells causes rapidly lethal autoimmunity. Pharmacologic inhibition of Usp7 impairs Treg but not conventional T cell function. Usp7 targeting alone, or in conjunction with other therapies, promotes anti-tumor immunity.T-regulatory (Treg) cells are essential to regulation of the immune system, and are characterized by their expression of the transcription factor, Foxp3. Foxp3 is subject to ubiquitination and degradation via the proteasome. We now show that the deubiquitinase, Usp7, is a key regulator of Foxp3 + Treg biology through controlling levels of the histone acetyltransferase, Tip60 and, to a lesser extent, Foxp3. Gene deletion or pharmacologic inhibition of Usp7 impairs Treg but not conventional T cell functions. The pharmacologic targeting of Usp7 alone, or in conjunction with additional therapeutic strategies, is of significant benefit in promoting host anti-tumor immunity.