Costimulatory signals, in addition to the T cell receptor engagement, are required for the optimal activation and survival of T lymphocytes. Lack of costimulatory activity may be responsible for immunological unresponsiveness to cancer. The overall goal of this study is to characterize cellular and molecular mechanisms of tumor immunity elicited by the costimulatory molecule 4-1BB (CDw137) and its ligand(4-1BBL). 4-1BBL belongs to the tumor necrosis factor (TNF) TNF receptor superfamily and are expressed primarily on activated T cells and antigen-presenting cells, respectively. The interaction of 4-1BB and 4-1BBL has been implicated in the costimulation of T cells. To this end, they have established mouse models in which engagement of 4-1BB by specific monoclonal antibodies induces immune responses leading to eradication of established large tumors. The primary effector cells for the immunity are CD4+, CD8+ T cells and natural killer (NK) cells. The central hypothesis of this proposal is that the 4-1BB pathway is required for the amplication of an ongoing immune response and lack of 4-1BB costimulation disrupts the process of tumor immunity. To test this hypothesis, they will examine the expression of 4-1BB on CD4+, CD8' T cells and NK cells during the early stage of tumor growth and identify the effector functions of key cellular components and cytokines in tumor immunity after direct 4-1BB ligation. In addition, they will explore the interaction between 4-1BB and B7-CD28 costimulatory pathways in order to enhance the activation of T cells and in antigen-presenting cells by transgenic techology can prevent the de novo development of cancer. It is anticipated that these studies will provide a foundation for the development of new approaches for the prevention and immunotherapy of cancers.
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