Cavalcanti Elisabetta, Gigante Margherita, Mancini Vito, Battaglia Michele, Ditonno Pasquale, Capobianco Carmela, Cincione Raffaele I, Selvaggi Francesco P, Herr Wolfgang, Storkus Walter J, Gesualdo Loreto, Ranieri Elena
Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
J Biomed Biotechnol. 2010;2010:935764. doi: 10.1155/2010/935764. Epub 2010 Mar 22.
To investigate the molecular mechanisms underlying altered T cell response in renal cell carcinoma (RCC) patients, we compared autologous and allogeneic CD8(+) T cell responses against RCC line from RCC patients and their HLA-matched donors, using mixed lymphocyte/tumor cell cultures (MLTCs). In addition, we analyzed the expression of molecules associated with cell cycle regulation. Autologous MLTC responder CD8(+) T cells showed cytotoxic activity against RCC cell lines; however the analysis of the distribution of CD8(+) T-cell subsets revealed that allogenic counterparts mediate superior antitumor efficacy. In RCC patients, a decreased proliferative response to tumor, associated with defects in JAK3/STAT5/6 expression that led to increased p27KIP1 expression and alterations in the cell cycle, was observed. These data define a molecular pathway involved in cell cycle regulation that is associated with the dysfunction of tumor-specific CD8(+) effector cells. If validated, this may define a therapeutic target in the setting of patients with RCC.
为了研究肾细胞癌（RCC）患者T细胞反应改变的分子机制，我们使用混合淋巴细胞/肿瘤细胞培养（MLTC），比较了RCC患者及其HLA匹配供体针对RCC细胞系的自体和异体CD8(+) T细胞反应。此外，我们分析了与细胞周期调控相关分子的表达。自体MLTC反应性CD8(+) T细胞对RCC细胞系表现出细胞毒性活性；然而，对CD8(+) T细胞亚群分布的分析显示，异体对应物介导了更强的抗肿瘤功效。在RCC患者中，观察到对肿瘤的增殖反应降低，这与JAK3/STAT5/6表达缺陷有关，导致p27KIP1表达增加和细胞周期改变。这些数据定义了一条参与细胞周期调控的分子途径，该途径与肿瘤特异性CD8(+)效应细胞功能障碍相关。如果得到验证，这可能为RCC患者确定一个治疗靶点。
