ABNORMAL TCR/CD3 SIGNAL TRANSDUCTION IN CANCER

由于不清楚的原因，肿瘤细胞经常不能触发足够的

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.