Engelhard, Victor H.
Professor, Microbiology, Immunology, and Cancer Biology
- BA, Biochemistry, Rice University, Houston, TX
- MS, Biochemistry, University of Illinois, Urbana, IL
- PhD, Biochemistry, University of Illinois, Urbana, IL
- Postdoc, Immunology, Harvard University, Cambridge, MA
Identification of MHC-restricted tumor antigens / Control of T cell homing to tumors / Role of lymphatic endothelial cells in regulating immunity and self-tolerance
Our research centers on understanding immune responses to tumors, and ways to enhance them for therapy. These responses depend on CD8 T lymphocytes, which recognize specific antigens on the tumor cell, leading to its destruction. Our work is in 3 areas. First, we identify antigens that tumor cells display. These antigens are small peptides produced by degradation of intracellular proteins, together with MHC molecules, which capture the peptides inside the cell and display them at the surface. Collaborating with Don Hunt in the Dept. of Chemistry, we developed mass spectrometry approaches to characterize the peptides displayed by MHC molecules. Recently, we identified phosphorylated peptides that are displayed on cancer cells, but not their normal counterparts. These peptides come from phosphoproteins associated with cellular signaling and growth control, and may be important targets for tumor immunotherapy. Many of these peptides are now in clinical trials at UVA as cancer vaccines. Second, we are pursuing the observation that many antigens on melanoma tumors are also on the normal cellular counterpart, the melanocyte. Immune responses against melanoma often lead to melanocyte destruction and autoimmune skin depigmentation. By using a transgenic mouse model, we have identified the mechanisms that establish self-tolerance to these antigens, but allow the persistence of cells that can recognize these melanoma/melanocyte antigens. We are trying to understand how the presence of tumors or vaccination alters self-tolerance, and the extent to which self-tolerance limits effective melanoma immunity. In the process, we have also discovered that lymph node stromal cells adventitiously express genes encoding antigens from other tissues, revealing a previously unknown mechanism of peripheral self-tolerance that we are investigating. Third, we are evaluating what controls the entry of T cells into tumors. A large fraction of tumors show no detectable lymphocyte infiltration, and these patients have a worse prognosis. We are discovering the molecules displayed on T cells, and their corresponding ligands on the tumor vasculature, to improve T cell infiltration as an important element of therapy.