Allergy and Immunology; Dermatology; Immunotherapy; Inflammation; Lymphocyte Activation; Lymphocytes; Medical Oncology; Neoplasms; Autoimmunity
Public Health Interests
Cancer; Immune functions
I am interested in 1) molecular, biochemical and functional aspects of cell surface costimulatory and coinhibitory molecules and 2) translation of laboratory findings to treat human cancer and autoimmune diseases.
Specialized Terms: Lymphocyte activation and tolerance; Costimulation and coinhibition; tumor microenvironment; Immunotherapy of human cancer and autoimmune diseases
Extensive Research Description
Co-signaling molecules (also called costimulatory and coinhibitory molecules, immune checkpoint molecules) are essential for T cell communication with virtually all other host cells. During cell-to-cell contact, a specific recognition occurs between receptors and ligands of these molecules, which triggers intracellular biochemical signals and leads 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.
-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
Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell-mediated immunity.
Flies DB, Han X, Higuchi T, Zheng LH, Sun JW, Ye JJ and Chen L. Coinhibitory receptor PD-1H preferentially suppresses CD4+ T cell-mediated immunity. Journal of Clinical Investigation 124(5):1966-1975, 2014
B7-H5 costimulates human T cells via CD28H.
Zhu Y, Yao S, Iliopoulou B, Han X, Augustine M, Xu H, Phennicie RT, Flies SJ, Broadwater M, Ruff W, Taube JM, Zheng LH, Luo L, Zhu G, Chen J and Chen L. B7-H5 costimulates human T cells via CD28H. Nature Communications 4:2043, 2013
Molecular mechanisms of T cell co-stimulation and co-inhibition.
Chen L and Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology 13:227-242, 2013
Advances in targeting of cell surface signaling molecules for immune modulation.
Yao S, Zhu Y and Chen L. Advances in targeting of cell surface signaling molecules for immune modulation. Nature Reviews Drug Discovery 12:130-146, 2013
Colocalizations of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanisms of immune escape.
Taube JM, Anders RA, Young GD, Xu HY, Sharma R, McMiller TL, Chen SM, Klein AP, Pardoll DM, Topalian SL and Chen L. Colocalizations of inflammatory response with B7-H1 expression in human melanocytic lesions supports an adaptive resistance mechanisms of immune escape. Science Translational Medicine 4:127-137, 2012. PMCID: PMC3568523
Anti-PD-1/PD-L1 therapy of human cancer: past, present and future.
Chen L and Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present and future. Journal of Clinical Investigation 125(9):3384-3391, 2015
PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations.
Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016 Mar 2;8(328):328rv4
B7-H2 is a costimulatory ligand for CD28 in human.
Sheng Y, Zhu Y, Zhu GF, Augustine M, Zheng LH, Goode DJ, Broadwater M, Ruff W, Flies S, Xu HY, Flies D, Luo LQ, Wang SD and Chen L. B7-H2 is a costimulatory ligand for CD28 in human. Immunity 34:729-740, 2011. PMCID: PMC3103603