Description of Research Program
Our program is dedicated to understanding the interaction between the immune system and cancer. Characterizing and quantifying the immune response to antigens in different disease states will be crucial to developing potential vaccine and immunotherapeutic strategies. Currently, our research program is divided into three distinct but interrelated areas of interest. These include studying dendritic cell biology, exploring approaches to break tolerance against self-antigens, and characterizing effector and memory T cells following tumor immunotherapy.
Dendritic Cell Function
Dendritic cells (DC) represent bone marrow-derived antigen presenting cells that are uniquely capable of initiating or modulating T cell immunity. Immature DC take up and process antigen with the peripheral tissue, but are inefficient in stimulating T cells. Upon maturation, DC migrate to secondary lymphoid tissues where they can prime both CD4 and CD8 T cell immunity. DC, however, are comprised of several different subsets, which maybe functionally distinct. Our group is interested in defining how different types of DC have different functional capacity in generating T cell immunity. By studying different DC subsets in different states of maturity, we hope to develop approaches to use DC as a means of inducing therapeutic antitumor immunity in vivo in both animal models and cancer patients.
We have performed multiple clinical trials using mature dendritic cells as a platform to immunize cancer patients to tumor-associated antigens. We have demonstrated that such an approach can lead not only to CD4 and CD8 T cell immunity, but to clinical responses as well. By studying human DC derived for these trials, we have been able to characterize human DC subsets in varying states of maturation. Currently, we are trying to explore the immunogenicity of different DC subsets in vivo in mice and humans. By exploring the immunomodulatory capacities of these different subsets, we hope to develop improved strategies for using DC to treat disease.
Tolerance to Tumor Associated Antigens
The majority of tumor-associated antigens represent self-antigens that are either aberrantly or overly expressed by the malignancy. As a result, the vast majority of solid tumors are not immunogenic. We have demonstrated in vivo in both animals and humans that immunizing with an "altered-self" can induce an autoimmune response against the relevant self-antigen. "Altered-self" can take the form of xenogeneic homologous of self-antigens to altered peptide ligands derived from self-antigens. Immunization with these antigens can induce cross-reactive immunity in a subset of cancer patients that can be associated with clinical responses.
In future studies, we hope to identify altered-peptide ligands derived from various self-antigens that are associated with solid tumor, and explore their immunogenicity in vivo in both animals and humans.
Evaluation of Antigen-specific T Cell Responses
The ability to identify the relevant cells involved in tumor regression can provide significant insight into improving tumor immunotherapeutic strategies. We have used different techniques to monitor patients with cancer and/or participating in our cancer vaccine trials. We have demonstrated that in vivo expansion of CD8 T cells identified with MHC/peptide tetramers can correlate with tumor responses in colon cancer patients. Current efforts underway are to characterize the T cell response following vaccination against tumor associated (self) antigens. By identifying the dynamics of antigen specific T cells and their capacity to develop immunologic memory, we hope to develop improved strategies in tumor immunotherapy.