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Oncotarget. 2017 Aug 19;8(44):77110-77120. doi: 10.18632/oncotarget.20363. eCollection 2017 Sep 29.

Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer.

Author information

1
Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, 80131 Naples, Italy.
2
Uro-Gynecological Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, 80131 Naples, Italy.
3
Department of Pharmacy, University of Naples Federico II, 80131 Naples, Italy.
4
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
5
Urology Division, University Federico II, 80131 Naples, Italy.

Abstract

With the intent to identify biomarkers in renal cell carcinoma (RCC) the functional status of T-regulatory cells (Tregs) was investigated in primary RCC. Tregs were isolated from tumoral-(TT), peritumoral tissue-(PT) and peripheral blood-(PB) of 42 primary RCC patients and function evaluated through effector T cells (Teff) proliferation, cytokines release and demethylation of Treg Specific Region (TSDR). The highest value of Tregs was detected in TT with the uppermost amount of effector-Tregs-(CD4+CD25hiFOXP3hiCD45RA-). PB-RCC Tregs efficiently suppress Teff proliferation compared to healthy donor (HD)-Tregs and, at the intrapatient evaluation, TT-derived Tregs were the most suppressive. Higher demethylation TSDR was detected in TT- and PB-RCC Tregs vs HD-Tregs (P <0,001). CXCR4 is highly expressed on Tregs, thus we wished to modulate Tregs function through CXCR4 inhibition. CXCR4 antagonism, elicited by a new peptidic antagonist, Peptide-R29, efficiently reversed Tregs suppression of Teff proliferation. Thus Tregs functional evaluation precisely reflects Tregs status and may be a reliable biomarker of tumoral immune response. In addition, treatment with CXCR4 antagonist, impairing Tregs function, could improve the anticancer immune response, in combination with conventional therapy and/or immunotherapy such as checkpoints inhibitors.

KEYWORDS:

CXCR4; T regulatory cells; immune suppression; renal cell carcinoma; tumor microenvironment

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no conflicts of interest.

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