Targeting CXCR4 impaired T regulatory function through PTEN in renal cancer patients

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2024年5月4日

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Sara Santagata,
Giuseppina Rea,
Anna Maria Bello,
Anna Capiluongo,
Maria Napolitano,
Sonia Desicato,
Alessandra Fragale,
Crescenzo D’Alterio,
Anna Maria Trotta,
Caterina Ieranò,
Luigi Portella,
Francesco Persico,
Marilena Di Napoli,
Salvatore Di Maro,
Florinda Feroce,
Rosa Azzaro,
Lucia Gabriele,
Nicola Longo,
Sandro Pignata,
Sisto Perdonà,
Stefania Scala

摘要

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 ^Nrp-1+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 ^Nrp-1+Tregs frequency, the release of IL-35, IL-10, and TGF-β1, while increased IFN-γ Teff-secretion. The CXCR4 ligand, CXCL12, recruited ^CD25+PTEN+Tregs in RCC while R54 significantly reduced it. IL-2/PMA activates Tregs reducing ^pAKT+Tregs while R54 increases it. The AKT inhibitor, TCB, prevented the increase in ^pAKT+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.