Abstract
Infiltrating T-regulatory cells in the tumor microenvironment is a key impediment to immunotherapy and is linked to a poor prognosis. We found that tumor-infiltrating Tregs express a higher expression of the chemokine receptor CCR4 than peripheral Tregs in breast cancer patients. CCL22 and CCL17 are released by tumor cells and tumor-associated macrophages, attracting CCR4+ Tregs to the tumor site. The Treg lineage-specific transcription factor FOXP3 changes the CCR4 promoter epigenetically in conjunction with HAT1 to provide a space for FOXP3 binding and activation of the CCR4 gene. To increase CCR4 expression in Tregs, the FOXP3/HAT1 axis is required for permissive (K23 and K27) or repressive (K14 and K18) acetylation of histone-3. In murine breast and melanoma tumor models, genetic ablation of FOXP3 reduced CCR4+ Treg infiltration and tumor size while also restoring anti-tumor immunity. Overexpression of FOXP3, on the other hand, increased CCR4+ Treg infiltration, resulting in a decreased anti-tumor immune response and tumor progression. These findings point to FOXP3 playing a new role in the tumor microenvironment as a transcriptional activator of CCR4 and a regulator of Treg infiltration.
Highlights
IntroductionTumor growth and development is a complex and dynamic process
FOXP3 was employed as an internal marker, while CD4, CD25, and CD127 were used as surface markers [33]
The two populations of Tregs (CCR4+ and CCR4-) are present in both healthy donors and tumor patients, according to CCR4 expression levels; the presence of the CCR4+ Treg population is higher than the CCR4- Treg population in tumor patients, which indicates that Treg increases the expression of
Summary
Tumor growth and development is a complex and dynamic process. Tumor microenvironment (TME), which is made up of a growing tumor mass, extracellular matrix, immune and stromal cells, and cell-secreted cytokines and chemokines, aids carcinogenesis [1]. Growing tumor mass alters the immune system, resulting in a tolerogenic environment in the TME [2, 3]. The development of FOXP3/HAT1 Induces CCR4 Expression in Tregs. T-regulatory (Treg) cells is the most important and meaningful change among them. Among the diverse immune cells, Treg cells are critical components that play a major role in tumor immunological escape [4]. Treg cells promote peripheral tolerance on the one hand, but their effects on tumor immunosurveillance are damaging on the other
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