School of Medicine
Bone Marrow and Stem Cell Transplantation Program
Leukemia, Lymphoma, and Myeloma Program
Area of interest
Our laboratory is interested in the mechanism by which T cells and antigen presenting cells migrate into tissues to mediate their function. We have focused on two areas that are important in cancer biology. Allogeneic stem cell transplantation is a common treatment for patients with refractory malignancies, however, the widespread use of this form of therapy is limited by the occurrence of graft-versus-host disease (GVHD). Our group was the first to show that chemokines are involved in the affector phase of GVHD (1). We followed this with a manuscript that demonstrated that T cells are the major source of CCL3 and that this chemokine had different effects on CD4+ and CD8+ T cells (2). We found that the chemokine receptor, CCR5, when absent on T cells leads to accelerated GVHD due to increased activity of the CXCL10/CXCR3 axis and perhaps impaired migration of CCR5-expressing Treg cells (3,4).
Our group was the first to demonstrate that chemokine receptors are critical in the migration of regulatory T cells during GVHD and that the inability of these cells to migrate to specific organs enhanced organ-specific GVHD (5). Our assessment of the function of specific proteins in migration during GVHD was recently published as a review in Blood in 2005. Quite recently, we were the first group to demonstrate that T cells polarized to the Th17 axis mediate significant GI tract, lung and skin GvHD (6) and that blocking the function of a specific chemokine receptor, CCR7, (7) or the NF-kappa B pathway (8) are pharmacological targets for the prevention of acute GvHD. Our current work focuses on the role of T cell subsets and proteins important in the migration of T cells in the biology of GvHD.
Most recently, we have focused on the function of immune cells that block the anti-tumor activity of other immune cells after cancer vaccination. We have found that regulatory T cells play an important role in this process (9). However, much of our work has focused on the role of myeloid-derived suppressor cells, which are immature myeloid cells, that block anti-tumor immunity. Recently, in collaboration with Jenny Ting, my co-leader for the immunology program, we found that NLRP3 blocks the function of cancer vaccines by inducing the recruitment of MDSCs to the tumor site (10). This important finding may offer new approaches to enhancing tumor vaccination. We have a long-standing collaboration with members of the CVI to evaluate viral vectors to induce anti-tumor immunity (11). Additionally, we have collaborated quite closely with the Van Deventer laboratory to investigate the mechanism by which immune-like cells potentiate the ability of metastatic tumor cells to grow in the lung (12).
Additionally our group and our collabortors have been the first to in vivo imaging of eGFP transgenic T cells as a method to track their migration in GVHD and their interaction with tumor cells in GvL (13, 14) and have recently begun to use intravital imaging to evaluate the interaction of APCs, T cells and regualtory T cells in the biology of GVHD.
Finally, we are enrolling patients on a trial designed to test the activity of vaccine therapy against HER-2/neu when combined with conventional therapy for patients with metastatic breast cancer. Early data from this trial has shown an improvement in survival in patients that develop an immune response to vaccination.
Awards and Honors
2003–Scientific Session on Advances in GVHD at American Society of Hematology
2005: Member SPORE Parent Committee
2005-present: Member Leukemia and Lymphoma Society TRP Grant Review Group
2006 Elizabeth Thomas Chair of Medicine, Microbiology and Immunology
2007-2010 Member TTT study section
2009-2012: Editorial Board Journal of Clinical Oncology
2011-present: Editorial Board Blood
2011: Presidential Symposium AAI Meeting San Francisco CA
2012: Plenary Session Presentation on Th17 Cells in Acute GVHD at American Society of Bone Marrow Transplantation Meeting
2012: Guest Associate Editor: Blood