Advances in Foxp3+ regulatory T cells (Foxp3+ Treg) and key factors in digestive malignancies

Abstract

Foxp3+ regulatory T cells (Foxp3+ Treg) play a role in regulating various types of tumors, but uncertainty still exists regarding the exact mechanism underlying Foxp3+ Treg activation in gastrointestinal malignancies. As of now, research has shown that Foxp3+ Treg expression, altered glucose metabolism, or a hypoxic tumor microenvironment all affect Foxp3+ Treg function in the bodies of tumor patients. Furthermore, it has been demonstrated that post-translational modifications are essential for mature Foxp3 to function properly. Additionally, a considerable number of non-coding RNAs (ncRNAs) have been implicated in the activation of the Foxp3 signaling pathway. These mechanisms regulating Foxp3 may one day serve as potential therapeutic targets for gastrointestinal malignancies. This review primarily focuses on the properties and capabilities of Foxp3 and Foxp3+Treg. It emphasizes the advancement of research on the regulatory mechanisms of Foxp3 in different malignant tumors of the digestive system, providing new insights for the exploration of anticancer treatments.

Keywords: FOXP3+ regulatory T cells; Foxp3; Foxp3 transcriptional and post-translational modifications; digestive system malignancies; immunotherapy targeting Foxp3+Treg.

Figure 1

Expression of Foxp3 in relation to T cells and cancer cells in the CRC tumor microenvironment. In colon cancer cells, Foxp3 and microRNA-155 work together to synergistically regulate the transcription of Zinc finger E-box binding homology box 2 (ZEB2), which suppresses ZEB2 expression and boosts anti-tumor immunity, reducing cancer cell growth and metastasis; In addition, Overexpression of Foxp3 also promotes MMP9 expression through the SAM cycle; The decrease of TCF-1 leads to an increase in the binding of Foxp3 to downstream gene regulatory elements, thereby promoting the expression of Treg, inhibiting the proliferation of effector T cells, and promoting the progression of CRC. ZEB2,the Zinc finger E-box binding homology box 2; MMP9, Matrix Metallo Protein 9; TCF-1,T Cell Transcription Factor 1.

Figure 2

The regulation of transcription and translation modifications related to Foxp3 in Foxp3+ Treg cells. The transcription of Foxp3 and the activation process of Foxp3 are regulated by binding to non-coding sequences such as c-Rel, ENO1, and Tet2, like CNS0-3, during transcription. In addition, the long non-coding RNA (lncRNA) Fricr is similar to the Foxp3 genome and can act in cis on the transcription process of Foxp3. Foxp3's post-translational regulation process mainly involves the methylation of PRMT1, glycosylation of PARP-1, cooperative ubiquitination of USP44 and USP7, dephosphorylation of PP1, acetylation regulation of SIRT1 and p300, and glucose metabolism process. The interaction of HIF-1α with Foxp3 protein and other factors can influence the expression and function of Foxp3. TGF-β, Transforming Growth Factor β; USP44, Ubiquitin Specific Peptidase 44; USP7, Ubiquitin Specific Peptidase 7; PRMT1, Protein arginine methyltransferase 1; PARP-1, Poly (adp-ribose) polymerase 1; PPI, Phosphoproteinase 1; TNF-α, Tumor necrosis factor-α; GLUT, The glucose transporter; VEGF, Vascular Endothelial Growth Factor; HIF-1α, Hypoxia-inducible factor-1α; Tet2, Tet methylcytosine dioxygenase 2.