THERAPEUTIC APPROACH TO PROTECT T CELLS FROM APOPTOSIS

描述：（申请人的摘要）肿瘤逃避免疫刺激的机制 破坏包括逃避策略，以避免免疫识别，以及 主动调节和抑制免疫细胞功能。申请人的 最近的研究表明，卵巢癌（OvCA）细胞能够 激活相互作用T细胞中程序性细胞死亡的内在机制 原位和体外淋巴细胞。这项研究的总体目标是描述 可能具有潜在治疗用途的保护机制， 肿瘤部位T淋巴细胞的不适当死亡。基于 根据申请人的初步研究，她假设死亡受体 在肿瘤相关淋巴细胞（TAL）上表达的蛋白被激活， 与卵巢癌细胞相互作用的淋巴细胞的细胞凋亡。 她进一步假设，观察到的凋亡细胞死亡可能是 通过用IL-2或IL-12细胞因子治疗来预防， 对淋巴细胞凋亡的内源性保护机制。测试 本研究提出以下具体目标：（1）研究 T细胞死亡受体在卵巢癌诱导的卵巢癌细胞凋亡中的作用 淋巴细胞;（2）确定细胞死亡的细胞内机制 在与卵巢癌细胞相互作用的T淋巴细胞中活化;（3） 鉴定内源性和马槟榔碱诱导抗凋亡机制， 保护淋巴细胞免受卵巢癌诱导的凋亡;（4）研究 腹腔内IL-2或IL-12激活淋巴细胞存活的机制 卵巢癌患者的治疗，作为同期I/II期研究的一部分 临床试验这些研究预计将提供深入了解的作用 淋巴细胞上的死亡受体在免疫抑制机制中的作用 在OvCA中运行。为了开发有效的癌症疗法，重要的是 阐明决定淋巴细胞对肿瘤介导的 细胞死亡以及它们的保护机制一个 了解这些机制对于开发有效的治疗方法是必不可少的 方案，这将使浸润淋巴细胞对肿瘤诱导的免疫应答产生抗性， 细胞凋亡和预防或逆转免疫低反应， OvCA患者

DESCRIPTION: (Applicant's Abstract) Mechanisms of tumor escape from immune destruction include evasive strategies to avoid immune recognition, as well as active modulation and suppression of immune cell function. The applicant's recent studies suggest that ovarian carcinoma (OvCA) cells are capable of activating an intrinsic mechanism of programmed cell-death in interacting T lymphocytes in situ and in vitro. The overall goal of the study is to delineate protective mechanisms that may have potential therapeutic use against inappropriate death of T lymphocytes at the tumor site. Based on the applicant's preliminary studies, she hypothesizes that death receptors expressed on tumor-associated lymphocytes (TAL) are activated to initiate an apoptotic cell death of the lymphocytes interacting with ovarian cancer cells. She further hypothesizes that the observed apoptotic cell death can be prevented by treatment with IL-2 or IL-12 cytokines, which upregulate activity of endogenous protective mechanisms against apoptosis of lymphocytes. To test this hypothesis, the following specific aims are proposed: (1) to investigate the role of death receptors on T cells in ovarian cancer-induced apoptosis of lymphocytes; (2) to identify the intracellular mechanisms of cell death activated in T lymphocytes interacting with ovarian cancer cells; (3) to identify endogenous and cytokine-induced anti-apoptotic mechanisms which can protect lymphocytes from ovarian cancer-induced apoptosis; (4) to investigate mechanisms of lymphocyte survival activated by intraperitoneal IL-2 or IL-12 therapy of patients with ovarian cancer, as a part of concurrent phase I/II clinical trials. These studies are expected to provide insights into the role played by death receptors on lymphocytes in immunosuppression mechanisms operated in OvCA. To develop an effective cancer therapy, it is important to elucidate what determines the susceptibility of lymphocytes to tumor-mediated cell death and what mechanisms are involved in their protection. An understanding of these mechanisms is essential for developing effective therapy regimens that would render infiltrating lymphocytes resistant to tumor-induced apoptosis and prevent or reverse the immune-hyporespsonsiveness seen in patients with OvCA.