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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.

由于尚不清楚的原因，肿瘤细胞常常无法触发足够的免疫反应。之前，我们表明可以刺激通过将 IL-2 基因直接引入肿瘤细胞来产生免疫反应使用逆转录病毒基因转移。虽然小鼠体内的肿瘤逐渐生长接种亲本 CMS5 肿瘤细胞，这些细胞经过基因工程改造，分泌的IL-2被排斥或生长缓慢。此外，有亲代的小鼠肿瘤，但不是那些生长缓慢、分泌IL-2的肿瘤免疫抑制，反映在生化和功能异常上。我们的工作假设是低水平的 PTK（例如 lck）会干扰具有多种 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 的招募以及随后导致的下游事件到细胞因子的合成。 lck 还激活 P13 激酶，然后将其结合与 CD28 一起进入共刺激通路。我们进一步建议体内肿瘤衍生的IL-2的分泌改变了结果否则淋巴细胞和肿瘤细胞之间的相互作用无效，可能是通过激活与 lL-2 的 β 链相关的 lck 受体。激活的 lck 的可用性使得能够启动下游事件导致 lL-2 的扩展和维护反应性抗肿瘤人群。肿瘤进展可能是结果之一亲代肿瘤携带者免疫反应下调的研究动物。在此应用中，我们将确定是否由于缺乏共刺激或缺乏 II 类有助于对 CMS5 无响应。其次，我们要判断是否减少了与 T 细胞激活相关的 PTK 水平与 T 细胞功能异常和信号转导改变转基因小鼠并通过比较依赖于的信号转导事件基于 PTK。第三，我们将确定潜在的分子机制 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 细胞功能的远端影响。这个独特的模型应该使我们能够检验我们的工作假设并获取有关潜在机制的重要信息免疫抑制可能会损害潜在的成功免疫疗法。这可能允许我们操纵局势优势。