Department of Microbiology and Immunology
Professor of Microbiology
I have over 25 years of experience with the design, development and use of immunodeficient mouse human tumor xenograft models to study the interaction of inflammatory leukocytes and fibroblasts with tumor cells in human lung and ovarian tumor microenvironments. My co-investigators and I have established that tumor-associated T cells are hypo-responsive to activation via the T cell receptor (TCR). We determined that the failure of these cells to respond to activation signals is due to the disruption of the TCR signaling cascade that occurs at or just proximal to the activation of PLC-γ. We have found that an identical TCR signaling arrest occurs in human T cells present within chronic inflammatory tissues. Using human tumor xenograft models my students and postdoctoral fellows established that a local and sustained release of IL-12 into the tumor microenvironment activates the quiescent tumor associated T cells to produce and secrete IFN-γ that mobilizes an immune mediated eradication of the tumor. Based upon these preclinical studies we have begun a Phase I clinical trial to test the safety and feasibility of delivering low and sustained doses of recombinant human IL-12 directly into patients’ tumors. Most recently we have determined that lipids present within human ovarian tumor ascites fluids mediate a reversible arrest in the TCR signaling pathway of ovarian tumor-associated T cells. A major focus of my laboratory is to structurally identify the immunoinhibitory factors present within the tumor ascites fluids, determine the mechanism by which they arrest the TCR signaling, and using a novel humanized mouse model to preclinically test whether the TCR signaling arrest can be reversed in tumor-associated T cells or prevented from occurring in T cells upon entry into the tumor microenvironment by eliminating or blocking the lipid mediated disruption of the TCR signaling cascade.