Inactivation of Cytotoxic Effectors in Oral Carcinomas

口腔癌中细胞毒性效应器的失活

• 批准号: 6516520
• 负责人: ANAHID JEWETT
• 金额: $ 21.71万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516520
• 关键词: DNA binding protein; JUN kinase; apoptosis; biological signal transduction; carcinoma; cell cell interaction; cytokine receptors; cytotoxic T lymphocyte; cytotoxicity; human tissue; immunosuppression; interferon gamma; natural killer cells; neoplasm /cancer immunology; neoplastic cell; neoplastic process; nuclear factor kappa beta; oral pharyngeal neoplasm; protein tyrosine kinase; receptor expression; transforming growth factors; tumor necrosis factor alpha

DESCRIPTION: The long-term objective of this application is to determine whether the initiation and progression of oral carcinomas in vivo is due to the induction of functional inactivation and cell death of Natural Killer cells. Human carcinomas of the head and neck and the oral cavity induce the least detectable cell-mediated anti-tumor immune responses, and decreased frequencies of proliferating lymphocytes have been observed in the peripheral blood and tumor tissue of oral cancer patients. More importantly, regressing oral tumors contain significantly larger numbers of functional NK cells when compared to those associated with primary tumors. Thus, the central hypothesis is that the initiation of NK cell apoptotic signaling by factors secreted from the NK cells or elaborated by oral cancer cells during their interaction will result in the inactivation of NK cell cytotoxic function, thereby enhancing the survival of oral carcinoma cells. To delineate the mechanisms by which Natural Killer cells lose their cytotoxic function and undergo apoptotic cell death in the presence of oral cancer cells, the following will be examined: 1. The role of oral tumor cell induced TNF-alpha release from NK cells in the absence of IFN-gamma secretion in inactivation and cell death of NK cells. There are also plans to study the effect of oral tumor cells on inhibition of TNF receptor associated protein (TRAFs) and NFkappaB functions in NK cells. 2. The effect of oral tumor cell elaborated TGF-beta on the inhibition of NFkappaB activity in NK cells, and subsequent induction of NK cell inactivation and cell death. 3. The roles of oral tumor cell induced stress related c-jun N-terminal kinase (JNK) and protein tyrosine phosphatase 1C (PTP1C) signaling in NK cells and in the regulation of TNF-alpha and NFkappaB and induction of NK cell inactivation and cell death by oral carcinoma cells. 4. The differential effects of sensitive and resistant oral carcinoma cells on NK cell inactivation and cell death. 5. The effect of patient derived oral tumor cells in NK cell inactivation and cell death. Using both in vitro established oral tumor lines and in vivo studies utilizing tumor tissues and immune cells from individuals with cancer of the oral cavity, the exact mechanisms by which oral carcinoma cells exert an immunosuppressive effect on NK cells will be examined. Understanding the mechanisms by which NK cells become functionally inactivated and undergo cell death will enable design strategies to reverse such inactivation and ensure effective immunity against oral tumor cells.

描述：此应用程序的长期目标是确定 口腔癌在体内的发生和发展是否是由于 自然杀伤细胞功能失活和细胞死亡的诱导。 人类头颈癌和口腔癌的诱因最小 可检测到的细胞介导的抗肿瘤免疫反应，频率降低 在外周血中观察到大量增殖的淋巴细胞 口腔癌患者的肿瘤组织。更重要的是，口腔肿瘤的消退 含有更多的功能性NK细胞，与 与原发肿瘤有关的肿瘤。因此，中心假设是 NK细胞分泌因子启动NK细胞凋亡信号转导 或口腔癌细胞在相互作用过程中所阐述的将导致 灭活NK细胞的细胞毒功能，从而提高存活率 口腔癌细胞。阐明自然杀伤细胞的作用机制 失去细胞毒性功能，并在存在的情况下经历凋亡细胞死亡 对于口腔癌细胞，将进行以下检查：1.口腔肿瘤的作用 细胞在缺乏干扰素-γ的情况下诱导NK细胞释放肿瘤坏死因子-α NK细胞失活和细胞死亡过程中的分泌。还有一些计划 口腔肿瘤细胞对肿瘤坏死因子受体相关抑制作用的研究 蛋白(TRAF)和NFkappaB在NK细胞中的功能。2.口腔肿瘤的影响 细胞阐述了转化生长因子-β对NK细胞中NFkappaB活性的抑制作用， 并随后诱导NK细胞失活和细胞死亡。3.角色 口腔肿瘤细胞诱导的应激相关c-jun氨基末端激酶(JNK)和 蛋白酪氨酸磷酸酶1C(PTP1C)信号在NK细胞中的表达 TNF-α和NFkappaB的调节及诱导NK细胞失活和 口腔癌细胞的细胞死亡。4.敏感度的差异效应 和耐药口腔癌细胞对NK细胞失活和细胞死亡的影响。5. 口腔肿瘤患者来源的肿瘤细胞对NK细胞失活及细胞的影响 死亡。使用体外建立的口腔肿瘤株和体内研究 利用肺癌患者的肿瘤组织和免疫细胞 口腔，口腔癌细胞发挥作用的确切机制 将检测对NK细胞的免疫抑制作用。了解 NK细胞功能失活和细胞死亡的机制 死亡将使设计策略能够逆转这种失活并确保 对口腔肿瘤细胞的有效免疫。