The Curcumin Analog GO-Y030 Controls the Generation and Stability of Regulatory T Cells

Abstract

Regulatory T cells (Tregs) play a crucial role in preventing antitumor immune responses in cancer tissues. Cancer tissues produce large amounts of transforming growth factor beta (TGF-β), which promotes the generation of Foxp3+ Tregs from naïve CD4+ T cells in the local tumor microenvironment. TGF-β activates nuclear factor kappa B (NF-κB)/p300 and SMAD signaling, which increases the number of acetylated histones at the Foxp3 locus and induces Foxp3 gene expression. TGF-β also helps stabilize Foxp3 expression. The curcumin analog and antitumor agent, GO-Y030, prevented the TGF-β-induced generation of Tregs by preventing p300 from accelerating NF-κB-induced Foxp3 expression. Moreover, the addition of GO-Y030 resulted in a significant reduction in the number of acetylated histones at the Foxp3 promoter and at the conserved noncoding sequence 1 regions that are generated in response to TGF-β. In vivo tumor models demonstrated that GO-Y030-treatment prevented tumor growth and reduced the Foxp3+ Tregs population in tumor-infiltrating lymphocytes. Therefore, GO-Y030 exerts a potent anticancer effect by controlling Treg generation and stability.

Curcumin analog GO‐Y030 boosts the efficacy of anti‐PD‐1 cancer immunotherapy

“…We reported that GO‐Y030–treated Tregs showed a low immune‐suppressive ability and produced more IL‐17A than DMSO‐treated Tregs. 9 We also reported that low doses of GO‐Y030 (0.25 μmol/L)‐treated Tregs did not promote cell death, but reduced the proliferation upon coculture with CD8+ T cells in vitro. 9 To address the mechanisms involved, we examined ROS expression in Tregs and found that ROS expression in GO‐Y030–treated Tregs was significantly higher than in curcumin‐treated and DMSO‐treated Tregs (Figure 1A,B ).…”

“… 9 We also reported that low doses of GO‐Y030 (0.25 μmol/L)‐treated Tregs did not promote cell death, but reduced the proliferation upon coculture with CD8+ T cells in vitro. 9 To address the mechanisms involved, we examined ROS expression in Tregs and found that ROS expression in GO‐Y030–treated Tregs was significantly higher than in curcumin‐treated and DMSO‐treated Tregs (Figure 1A,B ). In addition, OCR under basal conditions of GO‐Y030–treated Tregs was significantly lower than that of DMSO‐ and curcumin‐treated Tregs (Figure 1C,D ).…”

“…GO‐Y030–treated Tregs showed a Th17 phenotype and reduced the suppression ability without cell death and inhibitory proliferation. 9 We found that 0.25 μmol/L GO‐Y030 treatment did not significantly prevent T cell proliferation in the presence of TGF‐β+IL‐6 compared with DMSO treatment (Figure 2A ). In this setting, expression of RORγt, a master regulator of Th17, tended to be highly expressed in GO‐Y030 treatment, but there was no significant difference compared with DMSO and curcumin treatment (Figure 2B,C ).…”

“…GO‐Y030 is known to reduce the stability of mouse CD4 + CD25 + Tregs. 9 Using the fraction of human CD4 + CD25 + Tregs from peripheral blood mononuclear cells (Figure S1 A), we found that human CD4 + CD25 + Tregs were more resistant to the inhibition of cell proliferation by GO‐Y030 compared with mouse CD4 + CD25 + Tregs (Figure S1 B). We also found that GO‐Y030 treatment reduced Foxp3 expression in cultured human CD4 + CD25 + Tregs in a dose‐dependent manner (Figure S1 C).…”

“… 7 , 8 We have previously reported that GO‐Y030 represses the immune‐suppressive ability of Tregs via blockade of IL‐2 signaling. 9 As cellular stress, generated using 2‐deoxy glucose, inhibited TGF‐β–induced Treg, 10 it can be said that the metabolism of Tregs controls tumor immunity. Here, we found that GO‐Y030 induced cellular stress and prevented glycolysis in Tregs.…”