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

Sara Santagata, Maria Napolitano, Crescenzo D'Alterio, Sonia Desicato, Salvatore Di Maro, Luciana Marinelli, Alessandra Fragale, Maria Buoncervello, Francesco Persico, Lucia Gabriele, Ettore Novellino, Nicola Longo, Sandro Pignata, Sisto Perdonà, Stefania Scala

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)77110-77120
Number of pages11
JournalOncotarget
Volume8
Issue number44
DOIs
Publication statusPublished - Sep 29 2017

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    Santagata, S., Napolitano, M., D'Alterio, C., Desicato, S., Maro, S. D., Marinelli, L., Fragale, A., Buoncervello, M., Persico, F., Gabriele, L., Novellino, E., Longo, N., Pignata, S., Perdonà, S., & Scala, S. (2017). Targeting CXCR4 reverts the suppressive activity of T-regulatory cells in renal cancer. Oncotarget, 8(44), 77110-77120. https://doi.org/10.18632/oncotarget.20363