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

Autor: Santagata S; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Rea G; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Bello AM; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Capiluongo A; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Napolitano M; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Desicato S; Urology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Fragale A; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Rome, Italy., D'Alterio C; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Trotta AM; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Ieranò C; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Portella L; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Persico F; Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples 'Federico II', 80138, Napoli, Italy., Di Napoli M; Uro-gynecological Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Di Maro S; Department of Environmental, Biological and Pharmaceutical Science and Technology, University of Campania 'Luigi Vanvitelli', 81100, Caserta, Italy., Feroce F; Pathology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Azzaro R; Transfusion Medicine Unit, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Gabriele L; Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161, Rome, Italy., Longo N; Department of Neurosciences, Reproductive Sciences and Odontostomatology, Urology Unit, University of Naples 'Federico II', 80138, Napoli, Italy., Pignata S; Uro-gynecological Oncology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Perdonà S; Urology, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy., Scala S; Microenvironment Molecular Targets, Istituto Nazionale Tumori-IRCCS-Fondazione G. Pascale, 80131, Naples, Italy. s.scala@istitutotumori.na.it.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2024 Jun; Vol. 130 (12), pp. 2016-2026. Date of Electronic Publication: 2024 May 04.
DOI: 10.1038/s41416-024-02702-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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