Dr. Lieping Chen
Biochemical, structural and functional aspects of lymhocyte co-signal molecules; mechanisms of T lymphocyte activation and tolerance, cancer immunotherapy
Professor of Dermatology and Oncology
M.D., Fujian Medical School, Fuzhou, China Ph.D., Hahnemann Medical College, Philadelphia, PA
Resident in Medicine, Fujian Medical School, Fuzhou, ChinaOncology/Immunology Fellowship, Beijing Union Medical College, Beijing, China
Postdoctoral Fellowship, University of Washington/Bristol-Myers Squibb, Pharmaceutical Research Institute, Seattle, WA
A successful immune response consists of highly orchestrated cellular and molecular events. At the cellular level, a pathogen will first alert a set of so-called antigen-presenting cells (APC), including dendritic cells and macrophages, leading to stimulation of adaptive components of the immune systems, including T lymphocytes. Upon elimination of the pathogen, expanded T cells contract to basal level. At the molecular level, a pathogen is processed by APC and presented in the groove of the major histocompatibility complex (MHC) to T cells with a specific receptor (TCR) to initiate intracellular activation program. Outcome of the TCR signal, however, is largely determined by a group of co-signal molecules that are also presented on APC and T cells.
The research focus of our laboratory is to identify and characterize co-signal molecules that play key roles in the control of T-cell activation and deactivation. Co-signal molecules are essential for the communication of a T cell with virtually all other host cells. During cell-cell contact, specific recognition occurs between co-signal molecules and triggers biochemical signaling, which leads to cascades of transcription and expression of downstream genes in the nucleus. Therefore, co-signaling molecules are among the earliest responding elements of the immune system to antigens. A hallmark for co-signal molecules is that their functions are entirely dependent on TCR signals, and the role of co-signal molecules is to control the TCR signal. In the absence of sufficient TCR signaling, co-signal molecules lose their function or function aberrantly. The majority of co-signal molecules are members of the immunoglobulin (Ig) and tumor necrosis factor (TNF) superfamilies. Based on the functional outcomes, co-signal molecules can be further categorized as costimulators or positive costimulatory molecules that enhance TCR-mediated responses and coinhibitors or negative costimulatory molecules that inhibit TCR-mediated responses.
The main interest of our laboratory is biochemical, structural and functional studies of co-signal molecules. We are also interested in defining signaling events that induce activation and deactivation of naive and mature effector T cells. By precise manipulation of these cell-surface molecular pathways, we hope to develop new strategies to treat cancer, autoimmune diseases, viral infection, and transplantation rejection.
Woszczek, G., L. Y. Chen, S. Nagineni, S. Kern, J. Barb, P. J. Munson, C. Logun, R. L. Danner, and J. H. Shelhamer. 2007. Leukotriene D(4) induces gene expression in human monocytes through cysteinyl leukotriene type I receptor. J Allergy Clin Immunol.
Anand, S., Wang, P., Yoshimura, K., Choi, I. H., Hilliard, A., Chen, Y. H., Wang, C. R., Schulick, R., Flies, A. S., Flies, D. B., Zhu, G., Xu, Y., Pardoll, D. M., Chen, L. & Tamada, K. (2006). Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis. J Clin Invest 116, 1045-51.
Azuma, T., Yao, S., Zhu, G., Flies, A.S., Flies, S.J., and Chen, L. (2008). B7-H1 is a ubiquitous antiapoptotic receptor on cancer cells. Blood 111, 3635-3643.
Chen, L., Z. Zhang, W. Chen, Z. Zhang, Y. Li, M. Shi, J. Zhang, L. Chen, S. Wang, and F. S. Wang. 2007. B7-H1 up-regulation on myeloid dendritic cells significantly suppresses T cell immune function in patients with chronic hepatitis B. J Immunol 178:6634-41.
Crane, C., Panner, A., Murray, J.C., Wilson, S.P., Xu, H.Y., Chen, L., Simko, J.P., Waldman, F.M., Pieper, R.O., and Parsa, A.T. (2009). PI3 kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene. 28, 306-312.
Diehl, L., Schurich, A., Grochtmann, R., Hegenbarth, S., Chen, L., and Knolle, P.A. (2008). Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology 47, 296-305.
Flies, D. B. & Chen, L. (2006). Modulation of immune response by B7 family molecules in tumor microenvironments. Immunol Invest 35, 395-418.
Flies, D. B., and L. Chen. 2007. The new B7s: playing a pivotal role in tumor immunity. J Immunother (1997) 30:251-60.
Gallicchio, L., Matanoski, G., Tao, X. G., Chen, L., Lam, T. K., Boyd, K., Robinson, K. A., Balick, L., Mickelson, S., Caulfield, L. E., Herman, J. G., Guallar, E. & Alberg, A. J. (2006). Adulthood consumption of preserved and nonpreserved vegetables and the risk of nasopharyngeal carcinoma: a systematic review. Int J Cancer 119, 1125-35.
Goldberg, M. V., C. H. Maris, E. L. Hipkiss, A. S. Flies, L. Zhen, R. M. Tuder, J. F. Grosso, T. J. Harris, D. Getnet, K. A. Whartenby, D. G. Brockstedt, T. W. Dubensky, Jr., L. Chen, D. M. Pardoll, and C. G. Drake. 2007. Role of PD-1 and its ligand, B7-H1, in early fate decisions of CD8 T cells. Blood 110:186-92.
Han, A., He, J., Wu, Y., Liu, J. O. & Chen, L. (2005). Mechanism of recruitment of class II histone deacetylases by myocyte enhancer factor-2. J Mol Biol 345, 91-102.
Jeong, H.Y., Lee, Y.J., Seo, S.K., Lee, S.W., Park, S.J., Lee, J.N., Sohn, H.S., Yao, S., Chen, L., and Choi, I. (2008). Blocking of monocyte-associated B7-H1 (CD274) enhances HCV-specific T cell immunity in chronic hepatitis C infection. J Leukoc Biol 83, 755-764.
Kim, J., Myers, A. C., Chen, L., Pardoll, D. M., Truong-Tran, Q. A., Lane, A. P., McDyer, J. F., Fortuno, L. & Schleimer, R. P. (2005). Constitutive and inducible expression of b7 family of ligands by human airway epithelial cells. Am J Respir Cell Mol Biol 33, 280-9.
Kryczek, I., S. Wei, G. Zhu, L. Myers, P. Mottram, P. Cheng, L. Chen, G. Coukos, and W. Zou. 2007. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 67:8900-5.
Kryczek, I., Wei, S., Gong, W., Shu, X., Szeliga, W., Vatan, L., Chen, L., Wang, G., and Zou, W. (2008). Cutting edge: IFN-gamma enables APC to promote memory Th17 and abate Th1 cell development. J Immunol 181, 5842-5846.
Lafon, M., Megret, F., Meuth, S.G., Simon, O., Velandia Romero, M.L., Lafage, M., Chen, L., Alexopoulou, L., Flavell, R.A., Prehaud, C., and Wiendl, H. (2008). Detrimental contribution of the immuno-inhibitor B7-H1 to rabies virus encephalitis. J Immunol 180, 7506-7515.
Li, L., O. Piloto, K. T. Kim, Z. Ye, H. B. Nguyen, X. Yu, M. Levis, L. Cheng, and D. Small. 2007. FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells. Br J Haematol 137:64-75.
Malhotra, D., Thimmulappa, R., Navas-Acien, A., Sandford, A., Elliott, M., Singh, A., Chen, L., Zhuang, X., Hogg, J., Pare, P., Tuder, R.M., and Biswal, S. (2008). Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 178, 592-604.
Malhotra, D., Thimmulappa, R., Navas-Acien, A., Sandford, A., Elliott, M., Singh, A., Chen, L., Zhuang, X., Hogg, J., Pare, P., Tuder, R.M., and Biswal, S. (2008). Decline in NRF2-regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. American journal of respiratory and critical care medicine 178, 592-604.
McNamara, J., Kolonias D, Pastor F, Mittler R, Chen L, Giangrande PH, Sullenger B, Gilvoa E. 2008. Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J Clin Invest 118:376-386.
McNamara, J.O., Kolonias, D., Pastor, F., Mittler, R.S., Chen, L., Giangrande, P.H., Sullenger, B., and Gilboa, E. (2008). Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J Clin Invest 118, 376-386.
Melero, I., Martinez-Forero, I., Dubrot, J., Suarez, N., Palazon, A. and Chen, L. (2009). Palettes of vaccines and immunostimulatory monoclonal antibodies for combination. . Clin Cancer Res 15, 1507-1509.
Melero, I., S. Hervas-Stubbs, M. Glennie, D. M. Pardoll, and L. Chen. 2007. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer 7:95-106.
Mohamadzadeh, M., L. Chen, and A. L. Schmaljohn. 2007. How Ebola and Marburg viruses battle the immune system. Nat Rev Immunol 7:556-67.
Niu, L., S. Strahotin, B. Hewes, B. Zhang, Y. Zhang, D. Archer, T. Spencer, D. Dillehay, B. Kwon, L. Chen, A. T. Vella, and R. S. Mittler. 2007. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol 178:4194-213.
Olofsson, P.S., Soderstrom, L.A., Wagsater, D., Sheikine, Y., Ocaya, P., Lang, F., Rabu, C., Chen, L., Rudling, M., Aukrust, P., Hedin, U., Paulsson-Berne, G., Sirsjo, A., and Hansson, G.K. (2008). CD137 is expressed in human atherosclerosis and promotes development of plaque inflammation in hypercholesterolemic mice. Circulation 117, 1292-1301.
Ortler, S., Leder, C., Mittelbronn, M., Zozulya, A.L., Knolle, P.A., Chen, L., Kroner, A., and Wiendl, H. (2008). B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis. Eur J Immunol 38, 1734-1744.
Pentcheva-Hoang, T., L. Chen, D. M. Pardoll, and J. P. Allison. 2007. Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability. Proc Natl Acad Sci U S A 104:17765-70.
Pomper, M.G., Hammond, H., Yu, X., Ye, Z., Foss, C.A., Lin, D.D., Fox, J.J., and Cheng, L. (2008). Serial imaging of human embryonic stem-cell engraftment and teratoma formation in live mouse models. Cell Res.
Qian, D. Z., Y. F. Wei, X. Wang, Y. Kato, L. Cheng, and R. Pili. 2007. Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models. Prostate 67:1182-93.
Roseborough, G., Gao, D., Chen, L., Trush, M. A., Zhou, S., Williams, G. M. & Wei, C. (2006). The mitochondrial K-ATP channel opener, diazoxide, prevents ischemia-reperfusion injury in the rabbit spinal cord. Am J Pathol 168, 1443-51.
Schreiner, B., Bailey, S.L., Shin, T., Chen, L., and Miller, S.D. (2008). PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE. Eur J Immunol 38, 2706-2717.
Seo, S.K., Jeong, H.Y., Park, S.G., Lee, S.W., Choi, I.W., Chen, L., and Choi, I. (2008). Blockade of endogenous B7-H1 suppresses antibacterial protection after primary Listeria monocytogenes infection. Immunology 123, 90-99.
Talay, O., Shen, C.H., Chen, L. and Chen, J. (2009). B7-H1 on T cells is required for T cell-mediated conditioning of dendritic cells maturation. Proc Natl Acad Sci 106, 2741-2746.
Tamada, K. & Chen, L. (2006). Renewed interest in cancer immunotherapy with the tumor necrosis factor superfamily molecules. Cancer Immunol Immunother 55, 355-62.
Terme, M., Ullrich, E., Aymeric, L., Apetoh, L., Menard, C., Ghiringhelli, F., Viaud, S., Tesniere, A., Ryffel, B., Debey-Pascher, S., EggLe, D., Hurabain, I., Yagita, H., Azuma, M., Chen, L., Kaplanski, G., Chaput, N., Kroemer, G., Schultze, J.L. and Zitvogel, L. (2009). Regulatory NK cells: IL-18-elicited NK cells with immunosuppressive functions. Nature Medicine 180, 4679-4686.
Tsushima, F., S. Yao, T. Shin, A. Flies, S. Flies, H. Xu, K. Tamada, D. M. Pardoll, and L. Chen. 2007. Interaction between B7-H1 and PD-1 determines initiation and reversal of T-cell anergy. Blood 110:180-5.
Wahl, C., Bochtler, P., Chen, L., Schirmbeck, R., and Reimann, J. (2008). B7-H1 on hepatocytes facilitates priming of specific CD8 T cells but limits the specific recall of primed responses. Gastroenterology 135, 980-988.
Wei, S., Shreiner, A.B., Takeshita, N., Chen, L., Zou, W., and Chang, A.E. (2008). Tumor-induced immune suppression of in vivo effector T-cell priming is mediated by the B7-H1/PD-1 axis and transforming growth factor beta. Cancer Res 68, 5432-5438.
Wilcox, R., Chen L. 2007. CD137 [athway in innate and adaptive immunity, p. 85-97. In S. Khare (ed.), TNF Superfamily. R.G. Landes Bioscience Co., Austin,TX.
Xu, Y., A. S. Flies, D. B. Flies, G. Zhu, S. Anand, S. J. Flies, H. Xu, R. A. Anders, W. W. Hancock, L. Chen, and K. Tamada. 2007. Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease. Blood 109:4097-104.
Xu, Y., K. Tamada, and L. Chen. 2007. LIGHT-related molecular network in the regulation of innate and adaptive immunity. Immunol Res 37:17-32.
Yamashita, T., Tamura, H., Satoh, C., Shinya, E., Takahashi, H., Chen, L., Kondo, A., Tsuji, T., Dan, K. and Ogata, K. (2009). Functional B7.2 and B7-H2 molecules on myeloma cells are associated with a growth advantage. Clin Cancer Res 15, 770-777.
Yao, S. and Chen, L. (2008). Contribution of B7-H1/PD-1 co-Inhibitory pathway to T-cell dysfunction in cancer. In: Tumor Induced Immune Suppression, Mechanisms and Therapeutic Reversal., ed. D.I.G.A.A. Hurwitz, New York: Springer LLC, p29-40.
Yao, S., and Chen L. 2008. Contribution of B7-H1/PD-1 co-inhibitory pathway and T-cell dysfunction in cancer. In D. G. A. Hurwitz (ed.), Tumor Induced Immune Suppression. Springer, New York.
Zhu, G., Augustine, M.M., Azuma, T., Luo, L., Yao, S., Anand, S., Rietz, A.C., Huang, J.Q., Xu, H.Y., Flies, A.D., Flies, S.J., Tamada, K., Colonna, M., van Deursen, J.M.A. and Chen, L. (2009). B7-H4 deficient mice display augmented neutrophil-mediated innate immunity. Blood 113, 1759-1767.
Zhu, Y., and Chen, L. (2009). Turning the tide of lymphocyte costimulation. J Immunol 182, 2557-2558.
Zou, W., and Chen, L. (2008). Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8, 467-477.
Curiel, T. J., Coukos, G., Zou, L., Alvarez, X., Cheng, P., Mottram, P., et al. 2004. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10:942-949.
Dong, H., Zhu, G., Tamada, K., Flies, D. B., van Deursen, J. M. A., & Chen, L. 2004. B7-H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes. Immunity. 20:327-336.
Hirano, F., Kaneko, K., Tamura, H., Dong, H., Wang, S., Ichikawa, M., et al. 2005. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 65:1089-1096.
Thompson, R. H., Gillett, M. D., Cheville, J. C., Lohse, C. M., Dong, H., Webster, W. C., et al. 2004. Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc. Natl. Acad. Sci. USA. 101:17174-17179.
Zhang, X., Schwartz, J. D., Guo, X., Bhatia, S., Cao, E., Chen, L., et al. 2004. Structure and functional analysis of the costimulatory receptor programmed death-1. Immunity. 20:337-347.