William E. Gillanders, M.D.


Immunology Program

  • 314-747-0072

  • 314-362-4869

  • 314-454-5509

  • 8109

  • Suite 1160 NWT

  • gillandersw@wustl.edu

  • antigen presentation, breast cancer, translational research, T cells, vaccine

  • Development of a breast cancer vaccine

Research Abstract:

My current research interests are focused on breast cancer biology, immune therapy, and molecular genetics. As a physician scientist with a strong interest in translational research, not all of the projects in the laboratory would be appropriate for a graduate student or postdoctoral fellow. Included below is a short description of several ongoing projects in the laboratory.

Project #1 Defining pathways of antigen presentation following DNA vaccination.

DNA vaccination is a recently developed vaccine strategy to induce protective immune responses to infectious disease and cancer that has generated considerable enthusiasm. However, there are concerns about the potency of DNA vaccines. One of the limitations of DNA vaccination is the requirement for intracellular processing and presentation of encoded antigens by MHC class I molecules, a very inefficient process. This is of particular concern in the context of cancer vaccine development as many immunodominant peptides derived from self tumor antigens are not presented efficiently by MHC class I molecules. This inefficiency can be explained by the fact that surface expression of peptide-MHC complexes is influenced by a variety of factors, including efficiency of antigen processing, specificity of peptide translocation into the ER, and the biogenesis and kinetic stability of the peptide-MHC complex. To address these limitations, we have engineered completely assembled MHC class I peptide complexes in collaboration with Ted Hansen, Ph.D. whereby all three components of the complex (class I heavy chain, β2m, and peptide) are attached by flexible linkers. These engineered proteins are termed single chain trimers (SCT). In addition to the obvious clinical potential of SCT as DNA vaccines, these reagents have begun to provide unique insights into our understanding of the complex pathways of antigen presentation following DNA vaccination. Using SCT encoding epitopes that cannot be cross-presented, we have identified a novel pathway of antigen presentation following DNA vaccination.
Project #2: Defining the role of EpCAM in breast cancer invasion

Epithelial cell adhesion molecule (EpCAM) is a 40-kD cell-surface glycoprotein that is dramatically overexpressed in the majority of breast cancers. We were the first to demonstrate that EpCAM is directly involved in the regulation of breast cancer migration and invasion. Specifically, in loss-of-function studies we have demonstrated that specific ablation of EpCAM expression: (1) decreases breast cancer invasion in vitro and in vivo; (2) is associated with cytoskeletal rearrangement and alterations in Rho GTPases; and (3) impacts on the expression of transcription factors and genes known to be involved in breast cancer invasion. The hypothesis is that EpCAM plays a central role in the regulation of breast cancer invasion. We are currently exploring this hypothesis in detail using cultured human breast cancer cells, breast cancer xenografts, human breast specimens, and a transgenic mouse model of breast carcinogenesis. Specific aims include (1) Test the hypothesis that EpCAM plays a central role in the regulation of breast cancer invasion in vivo, using human breast cancer xenografts and human breast specimens; (2) Define the mechanism(s) by which EpCAM regulates breast cancer migration and invasion in cultured human breast cancer cells; and (3) Test the hypothesis that mammary tissue-specific expression of EpCAM alters breast cancer invasion in transgenic mice. EpCAM is currently under investigation as a potential target for molecular therapy in breast cancer. Defining the molecular mechanism(s) by which EpCAM facilitates breast cancer invasion will provide valuable insights into breast cancer biology, and may enhance our ability to translate novel molecular therapies into clinical practice.

Selected Publications:

Gillanders WE and Mohanakumar T. Progress in the development of a breast cancer vaccine: mammaglobin-A as an attractive target for vaccine therapy. Breast Diseases 2007 17: 26.

Salem ML, El-Naggar SA, Kadima A, Gillanders WE, and Cole DJ. The adjuvant effects of the toll-like receptor 3 ligand polyinosinic-cytidylic acid poly (I:C) on antigen-specific CD8+ T cell responses are partially dependent on NK cells with the induction of a beneficial cytokine milieu. Vaccine 2006 24: 5119.

Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE. EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Research 2004 64: 5818.

Salem ML, Kadima AN, Zhou Y, Nguyen CL, Rubinstein MP, Demcheva M, Vournakis JN, Cole DJ, Gillanders WE. Paracrine release of IL-12 stimulates IFN-gamma production and dramatically enhances the antigen-specific T-cell response after vaccination with a novel peptide-based cancer vaccine. Journal of Immunology 2004 172:5159.

Rubinstein MP, Kadima AN, Salem ML, Nguyen CL, Gillanders WE, Cole DJ. Systemic administration of IL-15 augments the antigen-specific primary CD8+ T cell response following vaccination with peptide-pulsed dendritic cells. Journal of Immunology 2002 169: 4928.

Last Updated: 8/3/2011 4:13:11 PM

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