Chief, Laboratory of Cancer Immunobiology, Robert W. Franz Cancer Research Center in the Earle A. Chiles Research Institute, Providence Health & Services
Clinical assistant professor, Department of Radiation Oncology, Oregon Health and Science University
Founder and Chief Scientific Office, Ubivac LLC, Portland, Oregon
Awards
American Cancer Society New Investigator Award, 2003-2007
National Cancer Institute, NIH, New Investigator Award, 2004-2009
Research Interests
The long-term goal of the Laboratory of Cancer Immunobiology is to develop vaccine strategies that lead to activation and expansion of therapeutic effector T cells in vivo to levels above the threshold required for tumor eradication and prevention of recurrence in tumor-bearing hosts. For most bacterial and viral infections, the robust innate and adaptive immune responses generally result in control of infection and development of a strong memory response. In contrast, for patients with cancer, the host immune system often fails to control the growth of cancer despite the fact that tumor cells replicate at a much slower rate than bacteria and viruses. The major differences between the immunology of infection and tumors include the following: tumor cells lack strong antigens; and tumor cells do not elicit a strong pro-inflammatory response (innate immunity), which orchestrates the subsequent adaptive immune response. The Laboratory of Cancer Immunobiology investigates novel approaches for compensating for this weak immunogenicity and breaking the tolerance of tumor self/normal antigens.
Current Projects
The Laboratory of Cancer Immunobiology is currently investigating whether a reduced threshold for T-cell activation in lymphopenic hosts will result in optimal activation and expansion of tumor-reactive CD4+ and CD8+ T cells when tumor antigens are presented by activated mature dendritic cells. Cross-presentation by host professional APC, such as dendritic cells, is believed to be the major pathway for tumor vaccine induced T-cell immune responses. The specific aims of this study are: to optimize the DC activation conditions for efficient cross-priming of tumor-specific T cells; to investigate efficacy of DC-based vaccines in RLM; to track the fate of tumor-specific CD8 T cells in RLM; and to investigate how CD4-help affect the fate of tumor-specific CD8 T-cells in vaccinated RLM.
Vaccination against tumors also might be very effective when antigens presented in the vaccines are ignored by host immune system. Tumor cells contain a large array of short-lived proteins are ignored by host immune system because are rapidly degraded and disposed thus could not be cross-presented by host dendritic cells and ignored by host immune system. Our hypothesis is that these short-lived proteins could elicit strong tumor-specific immune responses when they are cross-presented by mature dendritic cells in a sufficient quantity if their degradation could be prevented. Preliminary studies in our laboratory discovered that tumor cells are actively blebbing (Zeiosis) when they are treated with proteasome inhibitors. We refer to these zeiotic blebs as "DRibbles" because they contain ubiquitinated proteins possibly derived from defective ribosomal products (DRiPs) or other short-lived proteins (DRiPs in Blebs). DRibbles have induced a strong tumor-specific T-cell immunity and mediated tumor regression in several tumor models. Currently we are working to determine the underlining mechanisms that enable DRibbles to induce a strong therapeutic T-cell mediated antitumor immunity in tumor-bearing mice as a preliminary step in developing immune-based therapies for human cancers.
