University of Virginia Health System

Our research centers on understanding immune responses to tumors, and defining ways to enhance it for therapeutic purposes. Work by our lab and other has established that these immune responses are usually dependent on CD8 T lymphocytes, which recognize specific antigens displayed on the surface of the tumor cells. This recognition leads to the direct destruction of tumor cells, or enhances the overall inflammatory environment within the tumor to cause destruction by other mechanisms. Within this framework, our work is focused in 3 areas. First, we are engaged in identifying the antigens that tumor cells display, and that can be recognized by CD8 T lymphocytes. These antigens are created from two parts: small peptides, produced by the degradation of intracellular proteins, and proteins called MHC molecules, which capture these peptides inside the cell and display them at the cell surface. In collaboration with Dr. Donald Hunt in the Dept. of Chemistry and Dr. Craig Slingluff in the Dept of Surgery, we have developed mass spectrometry approaches for characterizing the complex mixture of peptides displayed by MHC molecules, and have defined a subset that are recognized by T cells during immune reactions to human melanoma tumor cells. Most recently, we have identified a set of phosphorylated peptides that are displayed on cancer cells, but not their normal counterparts. These peptides are derived from phosphoproteins associated with cellular signaling and transformation, suggesting that they may be particularly important targets for tumor immunotherapy. Many of the peptides we have identified are now being used in clinical trials at UVA to develop therapeutic vaccines for melanoma. Second, we are using transgenic mice that express human MHC molecules to model the human immune response to melanoma. This unique “preclinical” model is being used to systematically understand the quality of the response, the reasons that it ultimately fails to control melanoma, and to design and evaluate approaches to enhance effective immunity. The insights gained from this work can be used to accelerate progress in human clinical trials by identifying more useful approaches more rapidly than would otherwise be possible. Third, we are pursuing the intriguing observation that many of the antigens recognized on melanoma tumors by T lymphocytes are also expressed on the tumors normal cellular counterpart, the melanocyte. Indeed, immune responses against melanoma often lead to autoimmune skin depigmentation. Again, by using a transgenic mouse model, we are evaluating the mechanisms that establish self-tolerance to these antigens, and which nonetheless allow the persistence of cells that can recognize these melanoma/melanocyte antigens. In conjunction with this, we are trying to understand how the presence of melanoma tumors or vaccination alters the occurrence of self-tolerance, and the extent to which self-tolerance still limits effective melanoma immunity. are also expressed in normal tissue, this model allows us to evaluate the existence and impact of self-tolerance on effective anti-melanoma immune responses.

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