Cells in the human body communicate their health status to the immune system by degrading cellular proteins and presenting fragments of each on the cell surface in association class I MHC proteins. Appropriately educated, cytotoxic T-lymphocytes (CTL) (CD8+ T-cells) bind to the class I MHC molecules on the cell surface, sample the peptides being presented and kill those cells that express new peptides as a result of viral, bacterial and parasitic infection, tissue transplantation and cellular transformation (cancer). Presently, the most effective treatment for late stage metastatic melanoma involves adoptive cell therapy (ACT) with CD8+ T-cells. In this approach, tumor-infiltrating lymphocytes (TIL) are isolated from surgically removed tumor, expanded ex vivo and then re-introduced to the patient after ablation of his or her immune system by a combination of chemotherapy and total body irradiation. Efforts to improve this technology are in progress and involve transfecting patient CD8+ T-cells (prior to expansion) with high affinity receptors for specific tumor associated class I MHC peptides. With this additional step, it should be possible to use ACT to treat any human tumor. What is lacking are MHC class I peptides that are;(a) differentially displayed on cancer vs normal cells, (b) shared by large cohorts of patients with the same cancer (c) shared by multiple tumor types, (d) derived from proteins whose genes cannot be mutated or deleted without compromising tumor survival, and (e) not available for display on MHC molecules in the thymus or lymph nodes to trigger deletion of reactive CD8+ T-cells. Proposed here is research to develop new mass spectrometry instrumentation and methods for the identification of class I MHC phosphopeptides that are derived from dysregulated signal transduction pathways associated with cellular transformation characteristic of cancer cells and thus satisfy the above criteria. This research should make it possible to extend adoptive T-cell therapy to a number of other cancers including acute myeloid leukemia, chronic lymphocytic leukemia, pancreatic-,colorectal- and heptocellullar- adenocarcinoma and renal cancer.
PUBLIC HEALTHE RELEVANCE: Proposed here is research to develop new mass spectrometry instrumentation and methods for the identification of class I MHC phosphopeptides that are derived from dysregulated signal transduction pathways associated with cellular transformation. This research should make it possible to extend adoptive Tcell therapy beyond melanoma to other cancers including acute myeloid leukemia, chronic lymphocytic leukemia, pancreatic-, colorectal-, and heptocellullar adenocarcinoma and renal cancer.
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