Research ArticleCancer Immunotherapy

Foxo1 and Foxp1 play opposing roles in regulating the differentiation and antitumor activity of TH9 cells programmed by IL-7

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Sci. Signal.  10 Oct 2017:
Vol. 10, Issue 500, eaak9741
DOI: 10.1126/scisignal.aak9741

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Enhancing therapeutic potential

CD4+ T helper 9 (TH9) cells secrete the cytokines interleukin-9 (IL-9) and IL-21 and are important in cancer immunotherapy because of their ability to stimulate the antitumor effects of cytotoxic T cells. Bi et al. found that the presence of IL-7 in the culture medium during the differentiation process increased the production of TH9 cells in vitro and enhanced their antitumor activity. IL-7 signaling caused the exchange of the repressive transcriptional regulator Foxp1 for Foxo1 on the Il9 promoter, leading to increased Il9 expression and TH9 cell generation. Together, these results suggest that IL-7 treatment of TH9 cells may amplify the antitumor effects of this type of cancer immunotherapy.

Abstract

Tumor-specific CD4+ T helper 9 (TH9) cells, so-called because of their production of the cytokine interleukin-9 (IL-9), are a powerful effector T cell subset for cancer immunotherapy. We found that pretreatment of naïve CD4+ T cells with IL-7 further enhanced their differentiation into TH9 cells and augmented their antitumor activity. IL-7 markedly increased the abundance of the histone acetyltransferase p300 by activating the STAT5 and PI3K-AKT-mTOR signaling pathways and promoting the acetylation of histones at the Il9 promoter. As a result, the transcriptional regulator Foxo1 was dephosphorylated and translocated to the nucleus, bound to the Il9 promoter, and induced the production of IL-9 protein. In contrast, Foxp1, which bound to the Il9 promoter in naïve CD4+ T cells and inhibited Il9 expression, was outcompeted for binding to the Il9 promoter by Foxo1 and translocated to the cytoplasm. Furthermore, forced expression of Foxo1 or a deficiency in Foxp1 in CD4+ T cells markedly increased the production of IL-9, whereas a deficiency in Foxo1 inhibited the ability of IL-7 to enhance the differentiation and antitumor activity of TH9 cells. Thus, we identified the roles of Foxo1 as a positive regulator and Foxp1 as a negative regulator of TH9 cell differentiation and antitumor activity, which may provide potential targets for cancer immunotherapy.

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