Active Projects

1. T cell recognition of self- and neoantigens in tumor recognition and autoimmunity. We are working to identify specific properties of self, neoantigens and phospho-antigens and the corresponding T cells that promote optimal function and expansion with minmal autoimmune toxicity. Furthermore, we are developing a humanized MHC/TCR/CD8 transgenic mice by building artificial human chromosomes encoding human MHC and a full human TCR repertoires to identify novel neoantigen specific TCRs for adoptive T cell therapy in humans.

2. Mechanisms of initiation of T-cell signaling by the TCR-CD3 complex. Understanding how T-cell signaling is initiated, allows for the modulation of T-cell responses to cancer, infectious disease and autoimmunity and ultimately for the design of new and improved therapies. For example, our findings could aid in the design of better T-cell therapies such as chimeric antigen receptors therapies (CARs or synthetic TCRs) or aid the design of anti-TCR or CD3 antibodies or small molecule inhibitors for therapeutic use. In the translational aspect of this work we are working to identify specific TCR mutations that increase the interaction with CD3 using retroviral TCR display to provide precise guidance for therapeutic strategies by enhancing or decreasing the CD3 interaction that could be utilized for immunotherapy.

3. The regulation of T cell sensitivity, proximal signaling and mechanisms of resistance to immunotherapies during anti-tumor responses. We are investigating how TCR-proximal signaling pathways and negative inhibitors (PD-1, CTLA-4 and others) affect TCR-pMHC binding, mechanosensing and T-cell sensitivity thresholds in tumor immunity and autoimmunity. We are generating novel pre-clinical mouse models for evaluation of tumor response and immune therapy mediated toxicity.

4. Biomarkers for immune response and toxicity prediction. We use human clinical samples to identify biomarkers and new potential targets for immunotherapy and toxicity prediction. Finally, we are interested in how specific proteins in the tumor microenvironment can inhibit T cell signaling and migration to influence tumor immunity.

5. Covid-19 and T cell Immunity. We focus on of the role of T cells in protection against COVID-19, obtain a proof of concept for a novel COVID-19 vaccination strategy and determine the effect of checkpoint blockade on T cell responses during vaccination. We expect this research could lead to development of novel therapies and vaccines for treatment and prevention of COVID-19 infection.

Together, our studies have important implications for developing new therapies for cancer, viral and autoimmune disease, including direct possible applications to immunotherapy in humans.