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.
Highlights
Renal cell carcinomas (RCCs) is a disease with an estimated 338,000 new cases diagnosed worldwide [1] with approximately 30% of patients presenting with metastatic disease
T-regulatory cells (Tregs) isolated from primary tumor (TT), peritumoral tissue (PT) and peripheral blood (PB) of renal cancer (RCC) patients are highly activated
PB-Tregs from RCC patients cocultured with autologous T effector (Teff) cells more efficiently suppress Teff proliferation compared to healthy donor (HD)-Tregs (Figure 3A-3B)
Summary
Renal cell carcinomas (RCCs) is a disease with an estimated 338,000 new cases diagnosed worldwide [1] with approximately 30% of patients presenting with metastatic disease. T regulatory cells (Tregs) suppress a whole range of immune cells including B cells, NK cells, NKT cells, CD4+ or CD8+ T cells, monocytes and dendritic cells [4]. CTLA4 and PD-1 have been proposed as key molecules in generation and/or suppressive function of Tregs [11]. Cancer patients derived Tregs usually express a distinct profile of chemokine receptors, such as CCR4, CXCR4 and CCR5, which facilitates their migration into tumors in response to the corresponding chemokine ligands derived from tumor microenvironment [12]. With the intent to characterize the local antitumor immune response Tregs were functionally evaluated in 42 RCC patients. CXCR4 antagonism was investigated as a strategy to impair Treg efficiency
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