Professor of Inflammation and Epigenetics, Institute for Academic Medicine
Full Member, Research Institute
Director, Center for Inflammation & Epigenetics
Weill Cornell Medical College
Dr. Wang received his Ph.D. from the University of Georgia in 1992. After receiving his doctoral degree in Molecular Genetics, Dr. Wang expanded his field of expertise by training with Dr. James Mullins in the Department of Microbiology and Immunology at Stanford University School of Medicine. In 1994, Dr. Wang joined the Surgery Branch in the Center for Cancer Research at the National Cancer Institute (NCI) in Bethesda, Maryland where he worked with Branch Chief, Dr. Steve Rosenberg, who is a pioneer of cancer immunotherapy. In 1996, Dr. Wang was promoted to Senior Principal Investigator. During his tenure at the NCI, Dr. Wang made insightful discoveries on how immune cells recognize solid tumors through specific cancer antigens and published a landmark paper in Science on the development of a novel genetic approach to identify cancer antigens recognized by CD4+ T cells. In 2000, Dr. Wang was appointed Associate Professor at Baylor College of Medicine in the Center for Cell and Gene Therapy and the Department of Pathology and Immunology. He was promoted to full Professor in 2004. His lab studies novel mechanisms in tumor immunity and tolerance, innate immune regulation, regulatory T cell biology, inflammation, and epigenetics. He moved his laboratory to Houston Methodist Research Institute in 2011, where he currently serves as the Director of the Center for Inflammation and Epigenetics and Professor of Microbiology and Immunology, Weill Cornell Medicine, Cornell University. In recognition of his academic achievements, Dr. Wang received The Michael DeBakey Excellence in Research Award in 2006 and was bestowed with one of BCM’s highest honors; the Jack L. Titus Professorship in Pathology appointment in 2007-2011. Throughout his career Dr. Wang has published over hundred papers in the top class of journals, including Science, Cell, Nature Biotechnology, Nature Immunology, Cell Metabolism and Immunity, and has over 20 patents. His work has been supported by many grants from NIH, DoD, American Cancer Society, Cancer Research Institute and CPRIT.
Research interests in my laboratory include 1) cancer immunotherapy, 2) immune regulation in infectious and tumor immunity; 2) innate immune signaling and inflammation in diseases, 3) epigenetic reprogramming of cancer and immune cells.
1. Cancer immunotherapy
Cancer antigen and neoantigen discovery
Cancer immunotherapy has become the most promising approach to elimination and cure of malignant cancer. In the last few years, we have witnessed breakthrough of cancer immunotherapy. Checkpoint (PD-1/PD-L1) blockade therapy and engineered T cell immunotherapy using T cell receptor (TCR) or chimeric antigen receptor (CAR) have shown impressive and durable clinical responses against many types of cancer. Importantly, the clinical responses of these immunotherapies depend on T-cell recognition of tumor antigens, particularly mutation-derived neoantigens (Cell Research, 2017). The choice of immune targets is viral to success of immunotherapy, particularly for TCR/CAR-T therapy and vaccines. I have been working on cancer antigen discovery and immunotherapy for more than 20 years, and have identified many tumor antigens, including TRP1/2, NY-ESO-1, LAGE1, as well as many neoantigens (mutated CDC27, fusion protein and fibronection) that are recognized by CD4+ and CD8+ T cells. These findings have been published in Science (1999), JEM (1999 and 2002) and Immunity (2004). Development of a genetic targeting expression system has facilitated identification of many neoantigens recognized by antigen-specific CD4+ T cells derived from cancer tissues. Among these cancer targets, NY-ESO-1-specific T cell receptor (TCR) engineered T cell therapy has shown 55% of clinical response rate. NY-ESO-1 is one of the best antigens identified to date for immunotherapy of many solid cancers. Recently, we combined the exome- and RNA-seq with our targeting expression technology for rapid identification of somatic mutations and true neoantigens for personalized and tumor-specific immunotherapy.
Cancer vaccine and TCR/CAR-engineered T cell immunotherapy
Once tumor antigens and neoantigens are identified, both vaccine-based and TCR/CAR-T immunotherapies will be designed and applied to cancer patients. Our previous work shows that DC/peptide vaccines can induce strong antitumor immunity (Nature Biotechnology, 2002, JCI, 2004, Investigation of New Drugs, 2014).). We are currently working on NY-ESO-1 TCR-T cell immunotherapy as well as peptide/RNA-based vaccines. Despite impressive clinical response of checkpoint blockade therapy in many types of cancer, this therapy only shows limited (less than 20%) clinical response against breast cancer, prostate cancer, colon cancer and head-neck cancers. We intend to develop novel strategies for immunotherapy of these cancers by using neoantigen-specific vaccines and TCR immunotherapy, and how to improve CAR-T technology in the solid cancers.
Blockade of immune suppression to boost immunotherapy
Regulatory T cells (Treg) cells play a crucial role in maintaining immune homeostasis and self-tolerance. If immune response is activated and unchecked, it results in antoimmune diseases. There are several built-in immune checkpoints to negatively regulate immune response and keep delicate balance between immune response and immune tolerance. These checkpoint immune suppression mechanisms include CTLA-4 and PD-1/PD-L1 inhibitory signaling of T cell activation, regulatory T (Treg) and myeloid-derived suppressor cells. My team showed the presence of tumor-specific CD4+ Treg cells in cancer-derived tumor-infiltrating lymphocytes (Immunity, 2004, Immunity 2007)). Treg-mediated immune suppression at tumor sites may, at least in part, explain why current cancer vaccines induce only weak and transient immune responses and fail to produce therapeutic benefit. We are the first to demonstrate that human Toll-like receptor (TLR) 8 can reverses Treg cell function upon stimulation by it ligand, Poly-G3 oligonucleotide (Science 2005 and Immunity 2007). The use of TLR8 ligands to overcome Treg-mediated immune suppression may offer new opportunities to improve the outcome of cancer immunotherapy.
2. Innate Immune Signaling in cancer and infectious diseases
Innate immune signaling is activated by several classes of innate immune receptors, such as RNA (RIG-I, MDA5) and DNA (sGAS, AIM2) sensors, protects hosts from pathogens and modulates adaptive immune responses. We have identified several novel negative regulators (NLRC5, NLRX1, NLRP4, USP19, USP38, TRIM11 and TRIM14) that control NF-kB and type I interferon pathways and inflammation (Cell, 2010, Immunity 2011, Nature Immunology 2012, EMBO J. 2016, Molecular Cell, 2016, 2017). Increasing evidence suggests that inflammation induced by invading pathogens is a major driving force in the control or promotion of cancer development, and my group has defined a role for TAK1 in inflammation and colon cancer (Immunity, 2012). More recently, we show that two type I interferon signaling pathways operate in plasmacytoid dendritic cells (pDCs). Importantly, activation of cGAS-STING and MDA5-MAVS mediated IRF3-dependent type I interferon signaling pathway inhibits TLR7-MyD88-IRF7-mediated type I interferon pathway by upregulation of SOCS1 (Immunity, 2016). Our research will lead to better understanding of innate immune signaling and the development of more potent and effective vaccines against cancer and infectious diseases.
3. Epigenetic Reprogramming of iPSCs, Cancer and Immune cells
Although it is known that naïve T cells can be differentiated to different subsets of T cells through epigenetic regulation and cytokines, the molecular mechanisms are not clear. To address this issue, we identified Jmjd3 as a potent negative epigenetic regulator of somatic cell reprogramming and development (Cell, 2013, and PLoS Genetics, 2014), and further demonstrated that Jmjd3 functions as a critical epigenetic regulator in T cell differentiation and memory (Nature Communications 2015, and 2017). Further understanding of the epigenetic reprogramming of T cells will lead to the development of novel cancer therapeutics.