Douglas D Taylor
Department of Obstetrics Gynecology & Women's Health
University of Louisville School of Medicine, Clinical and Translational Research Building, USA
Dr. Douglas D Taylor obtained his B.S. in Chemistry & Biology from the University of Richmond. He obtained M.S in 1978. Ph.D. obtained from Wake Forest University Winston-Salem. Done Postdoctoral Fellowship from Department of Microbiology and Immunology, Boston University School of Medicine Boston.
The area of my research interests is Molecular Immunology and specifically focuses on immunologic recognition and pathways leading to the pro-inflammatory tumor microenvironment. In 1979, I published the initial discovery of circulating tumor-derived exosomes. These tumor-derived exosomes appear to mediate immune regulatory functions. Normally, exosomes serve as intercellular communication vehicles, regulating activation and differentiation events. Cells of the immune system utilize exosomes in elicit specific immune pathways, including activation of Th1 responses. Tumor-derived exosomes suppress these events resulting in tolerance to the tumor. Analyses of the immunologic responses of women to their cancers have identified aberrant immune recognition and response patterns and established evidence indicates that such aberrations pre-exists in these women and is genetically defined. Utilizing a combination of biochemical, molecular biological and molecular immunological techniques, the presence of gynecologic tumors have been shown to generate both cellular and humoral immune recognition within these patients; however, the effector responses in these women are generally suppressed. The presence of tumor-reactive antibodies and lymphocytes recognizing tumor-derived components demonstrates functional immune recognition; however, there appears to be a definitive shift to a Th2 response in these patients. We have subsequently shown that the clonal deletion of reactive T lymphocytes and the induction of an immunoglobulin response associated with gynecologic malignancies are analogous to the state induced during uncomplicated term pregnancies. As part of the integrated study, we have identified a selective suppression of effector T cells in women with gynecologic malignancies: loss of CD3-zeta. CD3-zeta is the primary activation signal transducing component associated with the T-cell receptor. In ovarian cancer, CD3-zeta expression on peripheral blood lymphocytes in suppressed 70-90%. This has directed our research to isolate and characterize the tumor-derived components responsible for this suppression. The components reside on exosomes actively released from the tumors. An additional focus of our research has been on the humoral aspects of the anti-tumor antibody response. While the shift to the Th2 response is ineffective in the eradication of a tumor, this humoral response appears to be directed against specific ovarian cancer antigens and
arising early in the timeline of tumor development. The induction of tumor-reactive immunoglobulins precedes the appearance of currently utilized tumor markers. In experimental animal models, this response was detectable soon after induction of the tumor, but prior to the development of a palpable tumor or clinical symptoms. Using the “autologous typing” technique coupled with sequencing by tandem mass spectrometry, several cellular proteins, which are commonly recognized by ovarian cancer patients, have been identified. Subsequently, a peptidespecific enzyme-linked immunosorbent assay technique was developed to identify the specific
altered epitopes that are recognized by the patients’ response. In contrast to the use of monoclonal antibodies, autologous tumor-reactive immunoglobulins recognize even single amino acid or carbohydrate alterations, as well as aberrant phosphorylation, on otherwise normal
proteins. Using procathepsin D as a model, we have identified specific epitopes commonly recognized by the humoral responses of ovarian cancer patients. Currently, investigations are analyzing the stage-associated appearance of specific protein alterations during the progression of
ovarian cancer using tumor-reactive IgG from patients at varying stage of disease. Ultimately, by identifying specific alterations appear early in the progression of cancer will allow development of early diagnostic assays. Identification of these epitopes will also provide a target for the development of immunotherapy. This work has lead to the filing of multiple patents and the
effort to commercialize the detection of tumor-reactive immunoglobulins diagnostically. The immediate benefit of this work is the development of an early, highly cancer-specific diagnostic assay. By identifying the shared recognition of specific epitopes, ultimately, the goal of this work is to identify epitopes for targeting vaccines.