Immune surveillance is a process by which T lymphocytes of the immune system detect and destroy transformed cells before they can become a threat to the host. This general idea is strongly supported by data directly demonstrating the presence of mutated proteins in some tumor cells that can serve as targets for immunological responses and tumor destruction. Thus, many tumors are visible to the immune system. Despite this, some tumors that are potentially visible by way of expressing mutated proteins still evade the immune response and kill the host. The process of tumor rejection by T lymphocytes requires the migration of the T cells from the blood into the tumor mass where contact dependent cytotoxic mechanisms and concentrated delivery of cytokines can be effective against the tumor. We hypothesize that one mechanism of failure of the immune response to reject tumors is failure to migrate to the tumor. To test this hypothesis we propose to image T cell migration to tumors using a targeted transgenic mouse and tumor model system combined with whole animal imaging technologies including MicroPET and MRI. The specific model is based on the DUC18 transgenic mouse that produces T cells that are focused on an antigen produced by the CMS-5 tumor cell. In preliminary experiments, we have shown that DUCl8 T cells efficiently reject the CMS-5 tumor implanted in mice. Thus, a critical next step is to study the migration of DUC18 T cells in live tumor bearing mice using radiotracer molecular imaging techniques. The project is divided into three specific aims. First; to use our MicroPET/MR techniques to study cell-mediated ablation kinetics of the implanted tumor model. Second; to investigate optical techniques to study tumor rejection and finally; to extend this research to include T cell ablation of a metastatic lung tumor model. DUCl8 T cells will be radiolabeled either internally or on surface receptors with targeted 64Cu chelates. Serial imaging of the radiolabeled cells will be achieved using MicroPET and co-registered with high-resolution MR images of the mice. This will allow for accurate measurement of the kinetics of cell distribution and tumor volume and subsequent MicroPET/MR imaging will be used to follow the ablation process over the following days. In addition, we will cross-validate new optical probes to monitor the process of T cell tumor ablation in these genetically engineered mice in vivo.
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