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 site immune modulation; 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
- Kohrt HE, Colevas AD, Houot R, Weiskopt K, Goldstein MJ, Lund P, Mueller A, Sagiv-Barfi I, Marabelle A, Lira R, Troutner E, Richards L, Rajapaska A, Hebb J, Chester C, Waller E, Ostashko A, Weng WK, Chen L, Czerwinski D, Fu YX, Sunwoo J and Levy R. Targeting CD137 enhances efficacy of cetuximab. Journal of Clinical Investigation 124(6):2668-2682, 2014
- 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
- 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
- Chen L and Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature Reviews Immunology 13:227-242, 2013
- Sznol M and Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clinical Cancer Research 19:1021-1034, 2013
- 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
- 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
- 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
- Zhu Y, Sheng Y and Chen L. Cell surface signaling molecules in the control of immune responses: A tide model. Immunity 34:466-478, 2011. PMCID: PMC3176719
- Azuma T, Zhu G, Xu HY, Rietz AC, Drake CG, Matteson EL and Chen L. Potential role of decoy B7-H4 in the pathogenesis of rheumatoid arthritis: A mouse model informed by clinical data. PLoS Medicine 6(10):e1000166, 2009. PMCID: PMC2760136
- Dong H, Zhu G, Tamada K, Flies DB, van Deursen JMA and Chen L. B7-H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. Immunity 20:327-336, 2004
- Sica GL,* Choi IH,* Zhu G, Tamada K, Wang S, Tamura H, Chapoval AI, Flies DB, Bajorath J and Chen L. B7-H4, a molecule of the B7 family, negatively regulates T-cell immunity. Immunity 18:849-861, 2003
- Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E and Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nature Medicine 8:793-800, 2002
- Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Dong H, Sica GL, Zhu G, Tamada K and Chen L. B7-H3: A costimulatory molecule for T cell activation and IFN-? production. Nature Immunology 2:269-274, 2001
- Dong H, Zhu G, Tamada K and Chen L. B7-H1, a third member of the B7 family, costimulates T cell proliferation and interleukin-10 secretion. Nature Medicine 5:1365-1369, 1999
- Melero I, Shuford WW, Newby SA, Aruffo A, Ledbetter JA, Hellström KE, Mittler R and Chen L. Monoclonal antibodies against the 4-1BB T cell activation molecule eradicate established tumors. Nature Medicine 3:682-685, 1997
- Chen L,* Ashe S, Brady W, Hellström I, Hellström KE, Ledbetter JA, McGowan P and Linsley PS. Costimulation of antitumor immunity by the B7 counterreceptor for T lymphocyte molecules CD28 and CTLA-4. Cell 71:1093-1102, 1992