ORAL CARCINOMA--SIGNAL TRANSDUCTION IN LYMPHOCYTES

口腔鳞状细胞癌（OSCC）的进行性生长 与对免疫反应的有害影响有关。我们有 表明肿瘤浸润淋巴细胞（TIL），肿瘤参与 淋巴结T淋巴细胞，在晚期疾病中还包括外周血 来自癌症患者的T淋巴细胞部分缺乏这种能力， 将刺激信号传递到细胞内部。这些 损伤与信号表达或功能的改变有关 转导分子TcR ζ链和p56 lck。基因工程的成功 免疫治疗方法依赖于TcR/CD 3信号转导缺陷的逆转 和免疫反应的恢复。一些研究表明 来自肿瘤宿主的缺陷T细胞并不是不可逆的， 损坏我们对接受生物治疗的癌症患者的观察 表明TcR ζ-链表达恢复与 对治疗的反应。该提案的目标是定义分子 口腔鳞状细胞癌免疫低反应的基础和机制 患者，并确定这些缺陷是否可以逆转生物 治疗我们建议表征TcR/CD 3的改变， 口腔鳞状细胞癌患者淋巴细胞信号通路的研究 这些变化与疾病分期、预后 和对治疗的反应待评价的生物疗法为：（i） 用IL-12转导的自体成纤维细胞进行局部治疗 基因和产生生物活性IL-12（项目3）;（ii）系统性 用IL-12蛋白治疗（项目3）;和（iii）用 野生型p53肿瘤抑制基因，其将在稍后引入 年的OSCC肿瘤表达突变型p53（项目2）。额外 将引入OSCC肽和DC的治疗（项目1和3） 在以后的岁月里。我们还建议调查潜在的机制 负责T细胞中zeta链表达水平的降低 口腔鳞状细胞癌患者的淋巴细胞。建议的实验策略是 我们观察到新鲜的肿瘤细胞诱导了部分损失， 对自体PL-T淋巴细胞体外培养过程中zeta链表达影响 共孵育。zeta链表达的减少似乎是 与淋巴细胞中肿瘤诱导的内源性蛋白水解过程有关， 由于用LLnL预处理自体T淋巴细胞， 蛋白酶抑制剂，阻断zeta-链的降解。因此， 假设内源性蛋白水解过程负责 口腔鳞癌患者T淋巴细胞ζ链缺陷。

Progressive growth of oral cavity squamous cell carcinoma of (OSCC) is associated with deleterious effects on the immune response. We have demonstrated that tumor-infiltrating lymphocytes (TIL), tumor involved lymph node T lymphocytes and, in advanced disease, also peripheral blood T lymphocytes from cancer patients are partially deficient in the ability to transmit stimulatory signals to the interior of the cell. These impairments are related to alterations in expression or function of signal transducing molecules TcR zeta-chain and p56 lck. Success of gene-or immunotherapy approaches depends on reversal of TcR/CD3 signaling defects and restoration of immune responsiveness. Several studies have suggested that defective T cells from tumor-bearing hosts were not irreversibly damaged. Our observations in cancer patients undergoing biologic therapies indicate that recovery in expression TcR zeta-chain correlates with response to therapy. The goal of this proposal is to define the molecular basis and mechanisms responsible for the immune hyporesponsiveness in OSCC patients, and determine whether these defects can be reversed by biologic therapies. We propose to characterize the alterations in the TcR/CD3 signaling pathway in lymphocytes from patient with OSCC and the relationship between these alterations and the disease stage, prognosis and response to therapy. The biologic therapies to be evaluated are:(i) locoregional therapy with autologous fibroblasts transduced with the IL-12 gene and producing biologically active IL-12 (Project 3); (ii) systemic therapy with IL-12 protein (Project 3); and (iii) local therapy with the wild-type p53 tumor suppressor gene, which will be introduced in later years into OSCC tumors expressing mutant p53 (Project 2). Additional therapies with OSCC peptides and DC (Project 1 and 3) will be introduced in later years. We also propose to investigate potential mechanisms responsible for the reduced level of expression of zeta-chain in T lymphocytes from OSCC patients. The proposed experimental strategy is supported by our observations that fresh tumor cells induce a partial loss in expression of zeta-chain in autologous PL-T lymphocytes during in vitro co-incubation. This reduction in zeta-chain expression appears to be related to tumor-induced endogenous proteolytic process in lymphocytes, since pretreatment of autologous T-lymphocytes with LLnL, a potent protease inhibitor, blocked the degradation of zeta-chain. We, therefore, hypothesize that an endogenous proteolytic process is responsible for the zeta-chain deficiency in T lymphocytes from patients with OSCC.