Lieping Chen MD, PhD
United Technologies Corporation Professor in Cancer Research and Professor of Immunobiology, of Dermatology and of Medicine (Medical Oncology); Director, Cancer Immunology Program at Yale Cancer Center
Co-signaling molecules; Costimulation; Coinhibition; Modulation of immune responses; Molecular mechanisms of lymphocyte activation and deactivation
-To understand the mechanisms of the B7-H1/PD-1 coinhibitory pathway in the evasion of tumor immunity
-Identification of new co-signaling (costimulatory and coinhibitory) molecules and their interactions
-Functional characterization of co-signaling molecules and their roles in the generation, development and regulation of immune responses to antigens
-Development of new approaches targeting new co-signaling pathways for the treatment of cancer, autoimmune diseases, inflammation and transplantation rejection in animal models
-Human immunology study to understand mechanisms of co-signal molecule-based therapy in cancer patients
The research focus of my laboratory is to understand molecular, biochemical and functional aspects of cell surface co-signaling molecule pathways (costimulation and coinhibition) in the control and modulation of immune responses to antigens. We are also interested in translating our laboratory findings to develop new treatment options for cancer, autoimmune diseases and inflammation.
Extensive Research Description
Co-signaling molecules with costimulatory and coinhibitory functions are essential for T cell communication with virtually all other host cells. During cell-to-cell contact, a specific recognition occurs between co-signaling receptors and ligands, which triggers intracellular biochemical signals that lead to the generation of immunological functions.
One hallmark of co-signaling molecules is that their function entirely depends on T cell receptor (TCR) signals. Co-signals positively and negatively control and modulate the initiation, expansion, functional maturation and execution, survival, and termination of T cell responses. The majority of co-signaling molecules are members of the immunoglobulin (Ig) and tumor necrosis factor (TNF) superfamilies. Our laboratory has identified a series of co-signaling molecules in both the B7-CD28 family (B7-H1/PD-L1, B7-H2/ICOSL, B7-DC/PD-L2, B7-H3 and B7-H4/B7x/B7S1) and the tumor necrosis factor (TNF) superfamily (CD137, LIGHT/HVEM) and characterized their biochemical pathways and immunological functions. We use monoclonal antibodies, recombinant co-signaling molecules, and gene knockouts to specifically manipulate co-signaling molecules.
Using mouse models, we have demonstrated the role of these co-signaling molecules in the pathogenesis and progression of various diseases, including cancer, autoimmune diseases, viral infections, and transplantation rejection. We have also developed several monoclonal antibodies which specifically stimulate (CD137) or inhibit (B7-H1, B7-H4) co-signaling molecule functions. These studies have laid the foundation for clinical trials that treat advanced cancer patients (anti-B7-H1/PD-L1, anti-PD-1, anti-CD137 antibodies) and autoimmune diseases (B7-H4Ig fusion protein). Ample evidence now supports that new strategies can be developed by precisely manipulating these cell surface molecular pathways to selectively block or promote T cell immunity in vivo as an approach to treat human diseases.
Currently, our laboratory is focusing on:
- The identification and characterization of new cell surface co-signaling molecules that control T cell priming, expansion, differentiation, memory, and survival: We have developed a Receptor Array system that rapidly identifies cell surface receptor-ligand interactions (Yao et al, Immunity, 2011). In combination with bioinformatic analysis, we perform genome-wide searches for new receptor-ligand interactions that are expressed during specific stages of T cell activation in response to antigen. These newly identified receptor-ligands will then be further characterized for their immunological function.
- The identification of intracellular biochemical pathways which determine the functional outcome of cell surface co-signaling: It is often difficult to interpret functional outcomes with specific intracellular signaling pathways due to the diverse effects that co-signaling can have on immune cells. We are developing new approaches to dissect complex signaling pathways that link cell surface co-signaling to extracellular immunological functions.
- Dissecting the mechanisms by which tumors escape the immune response: We are interested in the cellular and molecular mechanisms that determine a successful vs. a failed immune response in both animal models and human specimens, especially in the context of clinical trials that block the B7-H1/PD-1 pathway to treat human cancers.