Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity
Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock
Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock
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Research Article Immunology Oncology

Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity

Abstract

Foxp3+ Tregs are key to immune homeostasis, but the contributions of various large, multiprotein complexes that regulate gene expression remain unexplored. We analyzed the role in Tregs of the evolutionarily conserved CoREST complex, consisting of a scaffolding protein, Rcor1 or Rcor2, plus Hdac1 or Hdac2 and Lsd1 enzymes. Rcor1, Rcor2, and Lsd1 were physically associated with Foxp3, and mice with conditional deletion of Rcor1 in Foxp3+ Tregs had decreased proportions of Tregs in peripheral lymphoid tissues and increased Treg expression of IL-2 and IFN-γ compared with what was found in WT cells. Mice with conditional deletion of the gene encoding Rcor1 in their Tregs had reduced suppression of homeostatic proliferation, inability to maintain long-term allograft survival despite costimulation blockade, and enhanced antitumor immunity in syngeneic models. Comparable findings were seen in WT mice treated with CoREST complex bivalent inhibitors, which also altered the phenotype of human Tregs and impaired their suppressive function. Our data point to the potential for therapeutic modulation of Treg functions by pharmacologic targeting of enzymatic components of the CoREST complex and contribute to an understanding of the biochemical and molecular mechanisms by which Foxp3 represses large gene sets and maintains the unique properties of this key immune cell.

Authors

Yan Xiong, Liqing Wang, Eros Di Giorgio, Tatiana Akimova, Ulf H. Beier, Rongxiang Han, Matteo Trevisanut, Jay H. Kalin, Philip A. Cole, Wayne W. Hancock

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Figure 6

Rcor1 deletion impairs Treg function in vivo.

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Rcor1 deletion impairs Treg function in vivo. (A) The ability of Rcor1–...
(A) The ability of Rcor1–/– Tregs (0.5 × 106) to dampen homeostatic proliferation at 7 days after adoptive transfer of Teff cells (1 × 106) into Rag1–/– mice was significantly decreased compared with the effects of corresponding numbers of WT Tregs (P < 0.05). (B) The stability of YFP+ Rcor1–/– Tregs (1 × 106) at 4 weeks after adoptive transfer of Teff cells (0.25 × 106) in Rag1–/– mice was significantly decreased compared with the effects of corresponding WT Tregs, as shown by flow cytometric evaluation of viable cells. *P < 0.05; ***P < 0.001. (C) WT or Rcor1–/– mice (5 mice/group) received BALB/c cardiac allografts plus CD40L mAb/DST; long-term allograft survival was seen in WT but not Rcor1–/– recipients (P < 0.01). (D–I) Treg-specific deletion of Rcor1 enhanced antitumor immunity. Tumor volumes and AUC data of AE17 (D) and TC1 (G) lung tumors were smaller in syngeneic Rcor1–/– vs. WT mice (n = 8–10/group) after inoculation and reached statistical significance (P < 0.05). Analysis of CD4+Foxp3+, CD4+, CD8+, and CD8+IFN-γ+ cells in lymphoid tissues from Rcor1–/– or WT mice, bearing AE17 (E) or TC1 (H) tumors. qPCR analysis of gene expression of CD4, CD8, IFN-γ, granzyme B, and Foxp3 in tumor samples of AE17 (F) or TC1 (I) harvested at the end of each experiment. Data are shown as mean ± SD, 4–6 samples/group. Student’s t test for unpaired data. *P < 0.05; **P < 0.01; ***P < 0.005; ****P < 0.001 vs. WT control.