ABNORMAL TCR/CD3 SIGNAL TRANSDUCTION IN CANCER

癌症中 TCR/CD3 信号转导异常

基本信息

批准号：
2443072
负责人：
KAREN S ZIER
金额：
$ 20.84万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-07-01 至 1999-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2443072
关键词：
CD3 molecule MHC class II antigen T cell receptor anergy biological signal transduction immune tolerance /unresponsiveness interleukin 2 laboratory mouse leukocyte activation /transformation lymphokines neoplasm /cancer immunology protein biosynthesis protein tyrosine kinase surface antigens tissue /cell culture tumor antigens

项目摘要

For reasons that are unclear tumor cells often fail to trigger an adequate immune response. Previously, we showed that it was possible to stimulate an immune response by introducing the lL-2 gene directly into tumor cells using retroviral gene transfer. While tumors grew progressively in mice inoculated with parental CMS5 tumor cells, those genetically engineered to secrete lL-2 were rejected or grew slowly. Moreover, mice with parental tumors, but not those with slowly growing lL-2 secreting tumors were immunosuppressed, reflected in biochemical and functional abnormalities. Our working hypothesis is that low levels of PTKs such as lck interfere with several T cell activation pathways. For example, lck is responsible for phosphorylating the zeta chain of the TcR which is a prerequisite to the recruitment of ZAP- 70 and the subsequent downstream events that lead to cytokine synthesis. lck also activates P13-kinase which then associates with CD28, feeding into the costimulatory pathway. We further propose that the secretion of tumor derived lL-2 in vivo alters the outcome of the otherwise ineffective interaction between lymphocytes and tumor cells, possibly by activating lck associated with the beta chain of lL-2 receptor. The availability of activated lck enables the initiation of downstream events resulting in the expansion and maintenance of an lL-2 responsive anti-tumor population. Tumor progression may be one consequence of the downregulation of the immune response in parental tumor bearing animals. In this application, we will determine whether anergy due to the lack of costimulation or the absence of class II contributes to unresponsiveness to CMS5. Second, we will determine whether decreased levels of the PTKs associated with T cell activation are implicated in abnormal T cell function and altered signal transduction by using transgenic mice and by comparing signal transduction events that depend upon PTKs. Third, we will identify the molecular mechanisms underlying decreased expression of lck, fyn, and TcR zeta. Fourth, we will define distal consequences of abnormal signal transduction on T cell function. This unique model should enable us to test our working hypothesis and to obtain important information about mechanisms underlying the immunosuppression that can compromise potentially successful immunotherapies. This may permit the manipulation of the situation to our advantage.

由于不清楚的肿瘤细胞通常无法触发足够的原因免疫反应。以前，我们表明可以刺激通过将LL-2基因直接引入肿瘤细胞来进行免疫反应使用逆转录病毒基因转移。而肿瘤在小鼠中逐渐生长接种父母CMS5肿瘤细胞，这些细胞被基因设计为分泌的LL-2被拒绝或缓慢增长。而且，父母的老鼠肿瘤，但肿瘤的肿瘤却不是较慢的LL-2分泌肿瘤的肿瘤是免疫抑制，反映在生化和功能异常中。我们的工作假设是，低水平的PTK（例如LCK）干扰具有几个T细胞激活途径。例如，LCK负责用于磷酸化TCR的Zeta链，这是 ZAP-70的招募和随后领导的下游事件进行细胞因子合成。 LCK还激活p13-激酶，然后将其关联使用CD28，进食costumulation途径。我们进一步提出肿瘤衍生的LL-2体内的分泌改变了否则，淋巴细胞和肿瘤细胞之间的相互作用无效，可能通过激活与LL-2的β链相关的LCK 受体。活化的LCK的可用性使得下游事件导致LL-2的扩展和维护反应迅速的抗肿瘤人群。肿瘤进展可能是一个结果父母肿瘤轴承中免疫反应的下调动物。在此应用程序中，我们将确定是否由于缺乏共同刺激或缺乏II级有助于对CMS5无反应。其次，我们将确定是否减少与T细胞激活相关的PTK的水平与 T细胞功能异常和信号转导改变转基因小鼠和通过比较依赖的信号转导事件在PTK上。第三，我们将确定基础的分子机制 LCK，FYN和TCR ZETA的表达降低。第四，我们将定义异常信号转导对T细胞功能的远端后果。这个独特的模型应该使我们能够检验我们的工作假设和获取有关机制的重要信息可以损害潜在成功的免疫抑制免疫疗法。这可能允许对我们的情况操纵优势。