Santagata Sara, Napolitano Maria, D'Alterio Crescenzo, Desicato Sonia, Maro Salvatore Di, Marinelli Luciana, Fragale Alessandra, Buoncervello Maria, Persico Francesco, Gabriele Lucia, Novellino Ettore, Longo Nicola, Pignata Sandro, Perdonà Sisto, Scala Stefania
Functional Genomics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, 80131 Naples, Italy.
Uro-Gynecological Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione "G. Pascale"-IRCCS, 80131 Naples, Italy.
Oncotarget. 2017 Aug 19;8(44):77110-77120. doi: 10.18632/oncotarget.20363. eCollection 2017 Sep 29.
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-(CD4CD25FOXP3CD45RA). 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 ( <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.
为了在肾细胞癌（RCC）中鉴定生物标志物，研究了原发性RCC中调节性T细胞（Tregs）的功能状态。从42例原发性RCC患者的肿瘤组织（TT）、瘤周组织（PT）和外周血（PB）中分离出Tregs，并通过效应T细胞（Teff）增殖、细胞因子释放和Treg特异性区域（TSDR）的去甲基化来评估其功能。在TT中检测到Tregs的最高值，其中效应性Tregs（CD4CD25FOXP3CD45RA）的数量最多。与健康供体（HD）-Tregs相比，PB-RCC Tregs能有效抑制Teff增殖，并且在患者体内评估中，TT来源的Tregs抑制作用最强。与HD-Tregs相比，在TT-和PB-RCC Tregs中检测到更高的TSDR去甲基化（<0.001）。CXCR4在Tregs上高表达，因此我们希望通过抑制CXCR4来调节Tregs功能。一种新的肽拮抗剂Peptide-R29引起的CXCR4拮抗作用有效地逆转了Tregs对Teff增殖的抑制。因此，Tregs功能评估准确反映了Tregs状态，可能是肿瘤免疫反应的可靠生物标志物。此外，用CXCR4拮抗剂治疗损害Tregs功能，与传统疗法和/或免疫疗法（如检查点抑制剂）联合使用时，可改善抗癌免疫反应。
