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

Abstract

Foxp3 + T-regulatory (Treg) cells are known to suppress protective host immune responses to a wide variety of solid tumors, but their therapeutic targeting is largely restricted to their transient depletion or “secondary” modulation, e.g. using anti-CTLA-4 monoclonal antibody. Our ongoing studies of the post-translational modifications that regulate Foxp3 demonstrated that the histone/protein acetyltransferase, Tip60, plays a dominant role in promoting acetylation, dimerization and function in Treg cells. We now show that the ubiquitin-specific protease, Usp7, controls Treg function largely by stabilizing the expression and promoting the multimerization of Tip60 and Foxp3. Genetic or pharmacologic targeting of Usp7 impairs Foxp3 + Treg suppressive functions, while conventional T cell responses remain intact. As a result, pharmacologic inhibitors of Usp7 can limit tumor growth in immunocompetent mice, and promote the efficacy of antitumor vaccines and immune checkpoint therapy with anti-PD1 monoclonal antibody in murine models. Hence, pharmacologic therapy with Usp7 inhibitors may have an important role in future cancer immunotherapy.

The regulation of immune tolerance by FOXP3

“…81), thus improving the stability of FOXP3 and its association with the promoters of its target genes 24,79,80 . The inhibition or deletion of p300 reduces the levels of both acetylated and total FOXP3 in T reg cells, and negatively affects the fitness and function of these cells 81,82 . Importantly, p300 antagonism also undermines immune suppression in mouse models of cancer, thus enabling more robust antitumour immune responses that limit tumour growth 30 .…”

“…Importantly, p300 antagonism also undermines immune suppression in mouse models of cancer, thus enabling more robust antitumour immune responses that limit tumour growth 30 . The deletion of TIP60 also markedly decreases FOXP3 expression levels and leads to autoimmune pathology 81,82 . This T reg cell dysfunction is accompanied by a loss of FOXP3 dimerization, and TIP60-deficient T reg cells show reduced expression of FOXP3 and CTLA4, as well as inappropriate expression of the pro-inflammatory cytokines IL-6 and IL-17 (REF.…”

“…This T reg cell dysfunction is accompanied by a loss of FOXP3 dimerization, and TIP60-deficient T reg cells show reduced expression of FOXP3 and CTLA4, as well as inappropriate expression of the pro-inflammatory cytokines IL-6 and IL-17 (REF. 82). IL-6-induced STAT3 activity can downregulate the levels of the FOXP3 protein by inhibiting its acetylation 80,83 .…”

“…By contrast, overexpressing USP7 in T reg cells increases FOXP3 protein levels and augments T reg cell activity 104 . A recent study has revealed that the conditional deletion of USP7 in mouse T reg cells leads to a dramatic loss of immune regulation and to lethal autoimmunity within a month after birth 82 . This phenotype was associated with T reg cell hyperproliferation, disrupted T reg cell gene expression patterns, unstable FOXP3 protein levels and an ineffectual suppressive ability of T reg cells.…”

A Translational Perspective of a Deubiquitinase Inhibitor in Antitumor Immunity

“…However, most therapeutic trials can only partially deplete Treg cells or modulate Treg cell function indirectly (Pardoll, 2012). The work presented in this issue of EBioMedicine by Wang et al (2016) provides a new immunotherapy strategy against tumors by targeting Usp7, which successfully dampens the immune suppressive function of Treg cells and limits tumor growth.…”