AI Article Synopsis
- CXCR4 plays a significant role in regulating the trafficking of T regulatory cells (Tregs), and the new antagonist R54 was tested on Tregs from renal cell carcinoma (RCC) patients.
- In the study, R54 was found to impair the function of peripheral blood Tregs, decreasing their frequency and secretion of inhibitory cytokines while increasing effector T cell secretion of IFN-γ.
- The results suggest that targeting CXCR4 with R54 could effectively inhibit Treg activity in the tumor microenvironment of RCC by affecting key signaling pathways and Treg characteristics.
Article Abstract
Background: Tregs trafficking is controlled by CXCR4. In Renal Cell Carcinoma (RCC), the effect of the new CXCR4 antagonist, R54, was explored in peripheral blood (PB)-Tregs isolated from primary RCC patients.
Methods: PB-Tregs were isolated from 77 RCC patients and 38 healthy donors (HDs). CFSE-T effector-Tregs suppression assay, IL-35, IFN-γ, IL-10, TGF-β1 secretion, and Tregs frequency were evaluated. Tregs were characterised for CTLA-4, PD-1, CD40L, PTEN, CD25, TGF-β1, FOXP3, DNMT1 transcriptional profile. PTEN-pAKT signalling was evaluated in the presence of R54 and/or triciribine (TCB), an AKT inhibitor. Methylation of TSDR (Treg-Specific-Demethylated-Region) was conducted.
Results: R54 impaired PB-RCC-Tregs function, reduced Tregs frequency, the release of IL-35, IL-10, and TGF-β1, while increased IFN-γ Teff-secretion. The CXCR4 ligand, CXCL12, recruited Tregs in RCC while R54 significantly reduced it. IL-2/PMA activates Tregs reducing Tregs while R54 increases it. The AKT inhibitor, TCB, prevented the increase in Tregs R54-mediated. Moreover, R54 significantly reduced FOXP3-TSDR demethylation with DNMT1 and FOXP3 downregulation.
Conclusion: R54 impairs Tregs function in primary RCC patients targeting PTEN/PI3K/AKT pathway, reducing TSDR demethylation and FOXP3 and DNMT1 expression. Thus, CXCR4 targeting is a strategy to inhibit Tregs activity in the RCC tumour microenvironment.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11183124 | PMC |
| http://dx.doi.org/10.1038/s41416-024-02702-x | DOI Listing |
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