NFKB DEFECT AND APOPTOSIS IN T CELLS OF CANCER PATIENTS

描述(改编自《调查员摘要》)： 肾脏病患者有效的抗肿瘤免疫反应受损 细胞癌(RCC)。肿瘤浸润性淋巴细胞(TIL)已被 以功能受损为特征的，并表现出较差的诱导 转录因子，NFKB。肿瘤诱导的细胞凋亡可能是原因之一 与免疫抑制有关的因素，如我们实验室的原位TUNEL分析 表明肿瘤床内15%的CD3+细胞是凋亡的。 肾细胞癌也可能对T细胞产生全身性影响的观点是 据观察，60%的人外周血中的T细胞 这些患者在NFKB激活方面存在缺陷。最近的研究也 显示40%的肾癌患者外周血T细胞是 对激活诱导的细胞死亡(AICD)高度敏感。我们假设 NFKB活化受损与T细胞凋亡敏感性增加 肾细胞癌患者免疫功能障碍导致肿瘤 进展和较差的临床结果。这里提出的实验将需要 克利夫兰诊所大量肾癌患者的优势 基金会。AIM1将确定NFKB激活缺陷和 对AICD的易感性是患者T细胞中的相关现象。这将是 包括检测AICD易感性和AICD易感性之间存在相关性 受损的NFKB活性以及纯化的T细胞亚群是否表达 缺陷也表现为另一种。其他实验将确定这一点是否 事实上，连锁是由依赖于NFKB的表达下调所介导的 抗凋亡基因产物在AICD易感细胞中的表达 当RCC T有缺陷时，电阻与NFKB激活一样，恢复正常 细胞是在体外培养的。特征性较好的Fas和 此外，还将评估肾癌T细胞AICD易感性中的TNFR通路， 由于这些受体的促凋亡配体已知可在 一种独立于NFKB的时尚。目标2将把分子研究结果联系起来 获得了患者在目标1到几个临床相关免疫指标 功能。具体地说，拟议的实验将决定 NFKB活性缺陷和对AICD的敏感性与DTH受损相关 转移性肾癌患者的反应性和生存率下降。这 评估还将涉及对选定的抗凋亡基因的分析。这些 研究应评估NFkappaB缺陷和AICD敏感性是否 与患者的结果相联系和关联。

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.