NFKB DEFECT AND APOPTOSIS IN T CELLS OF CANCER PATIENTS

描述（改编自研究者摘要）： 有效的抗肿瘤免疫应答在肾肿瘤患者中受损， 细胞癌（RCC）。肿瘤浸润淋巴细胞（TIL）已被证实是 其特征在于功能受损并显示出对 转录因子NF κ B。肿瘤诱导的细胞凋亡可能是一个贡献 这种免疫抑制的因素，如原位TUNEL检测，从我们的实验室 表明肿瘤床内15%的CD3+细胞是凋亡的。 RCC也可能介导对T细胞的系统性作用的概念是 观察表明，60%的人的外周血T细胞 这些患者在NF κ B活化方面有缺陷。最近的研究还 研究表明，40%的RCC患者的外周血T细胞 对活化诱导细胞死亡（AICD）高度敏感。我们假设 NF κ B活化受损和T细胞凋亡敏感性增加 导致肾细胞癌患者的免疫功能紊乱， 进展和不良临床结局。这里提出的实验将 克利夫兰诊所的大型RCC患者群体的优势 基金会Aim1将确定NF κ B激活缺陷和 对AICD易感性是患者T细胞中的相关现象。这将 包括检验AICD易感性与 受损的NF κ B活化和纯化的T细胞亚群是否表达一种 缺点也表示其他。其他实验将确定这是否 事实上，这种连接是通过抑制NF κ B依赖性转录因子的表达介导的。 AICD易感细胞中的抗凋亡基因产物， 当有缺陷的RCC T时，抵抗力（如NFKB激活）恢复正常 在体外培养细胞。参与的良好表征的Fas和 将另外评估RCC T细胞AICD易感性中的TNFR途径， 因为已知这些受体的促凋亡配体在细胞中是可诱导的， 一种NFKB独立的方式。目标2将分子发现与 目的1中的患者获得了几种免疫相关的临床指标， 功能具体来说，拟议的实验将确定是否 NFkB活性缺陷和对AICD敏感性与DTH受损相关 转移性肾细胞癌患者的反应性和生存率下降。这 评估还将包括对选择的抗凋亡基因的分析。这些 研究应评估NF κ B和AICD敏感性的缺陷是否 与患者结局相关。

DESCRIPTION (As Adapted From the Investigator's Abstract): The development of an effective anti-tumor immune response is compromised in patients with renal cell carcinoma (RCC). Tumor infiltrating lymphocytes (TIL) have been characterized as functionally impaired and displaying poor induction of the transcription factor, NFKB. Tumor-induced apoptosis may be a contributing factor to this immunosuppression, as in situ TUNEL assays from our laboratory indicate that 15 percent of the CD3+ cells within the tumor bed are apoptotic. The notion that RCC may also be mediating a systemic effect on T cells is suggested by the observation that peripheral blood T cells from 60 percent of these patients are defective in NFKB activation. Recent studies also demonstrated that peripheral blood T cells from 40 percent of RCC patients are highly susceptible to activation-induced cell death (AICD). We hypothesize that impaired NFKB activation and increased sensitivity of T cells apoptosis contribute to the immune dysfunction in RCC patients which results in tumor progression and poor clinical outcome. The experiments proposed here will take advantage of the large RCC patient population at the Cleveland Clinic Foundation. Aim1 will determine whether the NFKB activation defect and susceptibility to AICD are related phenomena in patient T cells. This will include testing of a correlation exists between AICD susceptibility and impaired NFKB activation and whether purified T cell subsets expressing one defect also express the other. Other experiments will determine whether this linkage is in fact mediated by depressed expression of the NFKB -dependent anti-apoptotic gene products in AICD susceptible cells, and whether AICD resistance, like the NFKB activation, returns to normal when defective RCC T cells are cultured in vitro. The involvement of the well characterized Fas and TNFR pathways in RCC T cell AICD susceptibility will additionally be assessed, as the pro-apoptotic ligands for these receptors are known to be inducible in an NFKB-independent fashion. Aim 2 will correlate the molecular findings obtained for patients in Aim 1 to several clinical correlates of immune function. Specifically, the proposed experiments will determine whether the defect in NFKB activity and sensitivity to AICD correlate with impaired DTH responsiveness and decreased survival in patients with metastatic RCC. This assessment will also involve an analysis of select anti-apoptotic genes. These studies should assess whether the defect in NFkappaB and AICD sensitivity are linked and relate to patient outcome.