T lymphocytes play a central role in the initiation and regulation of the adaptive immune response to antigen, whether foreign or native. The outcome of T cell engagement of antigen is determined by both positive costimulation and negative coinhibition, generated mainly by the interaction between the B7 ligand family and their receptor CD28 family. We have discovered new members of the T cell costimulatory/coinhibitory B7 family and CD28 family including B7x, HHLA2 and TMIGD2, have identified KIR3DL3 (an orphan member of the KIR family) as a receptor for HHLA2, and have contributed to other immune checkpoints ICOS, PD-L1/PD-1, B7-H3, Tim-3, BTNL2, etc. We are using a variety of experimental approaches (gene knock-out/transgenic mice, humanized mice, monoclonal antibodies, single-cell RNA sequencing, crystal structure, patients samples, etc) to understand how new immune checkpoints regulate T cell and other immune cell activation and tolerance. Current emphasis in the lab is placed in the following areas: 1) Novel drugs development: Translational medicine of new immune checkpoints; 2) In vivo functions of new immune checkpoint pathways; 3) Human cancer-associated new B7/CD28 pathways and cancer immunotherapy; 4) Roles of new immune checkpoint pathways in autoimmune diseases/metabolic diseases and immunotherapy; 5) Relationship between new B7/CD28 pathways and infection; 6) Functional and structural characterization of new members of the immunoglobulin superfamily.
Our goal is to elucidate the mechanisms by which new immune checkpoints regulate T cells and other immune cells in peripheral non-lymphoid organs, and to translate the lessons learned in these studies towards developing new therapeutic strategies for cancers, autoimmune disorders, metabolic diseases, infectious diseases, and transplantation rejection.
Our research has formed scientific foundation and core intellectual property for several start-up drug companies. A novel immune checkpoint inhibitor derived from our lab is currently in clinical trials to treat cancer patients who have failed standard treatments or lack effective treatments. Another novel immune checkpoint inhibitor derived from our lab is expected to start clinical trials in 2023.
Since 2008 the lab has mentored total 45 trainees of MD-PhD or PhD students, postdoctoral fellows, clinical fellows, and visiting scientists. Most of trainees have subsequently moved on to independent careers in academic universities, medical centers, biopharmaceutical industry, and US government agencies.