Theodore H. Welling III, M.D.
Assistant Professor of Surgery
1500 E. Medical Center Dr.
2850B Taubman Center
Ann Arbor, MI 48109-5531
Our lab performs translational research focused on trying to understand the immunologic mechanisms involved with initiation and development of human liver cancers. The goal is to identify novel immunologic processes involved in liver tumor development that will lead to the discovery of new immunotherapies to treat liver cancers. In addition, pharmacologic targeting of these mechanisms within the liver microenvironment may also be developed. We have three major projects in the lab:
1) Hepatocellular Carcinoma. Hepatocellular carcinoma (HCC) is currently the fifth most common malignancy and the second most common cause of cancer related deaths in the world. While HCC is the most common primary liver malignancy in the world, the U.S. incidence has also been rising. Recurrence following treatment is common, occurring in 20-40% of patients undergoing liver transplantation or resection. The role of T regulatory cells, antigen presenting cells (APC), and interleukin-17 (IL-17) producing cells in the liver microenvironment is being examined in human HCC tissues. Specifically, the role of cell surface expression molecules involved in co-stimulation, regulation, or anergy are being studied with the use of flow cytometry, RT-PCR, in vitro assays, xenograft and genetic knockout murine models. Recent data generated in our lab from human HCC, human cholangiocarcinoma, and human colorectal metastasis point to a complex interaction between IL-17 producing cells, APCs capable of suppressive properties, and T regulatory cells.
2) Liver Cancer Stem Cells and Immune Response. Recently the cancer stem cell hypothesis has been shown to be important in breast, colon, pancreas, and also liver cancers. We are actively working on the isolation of liver cancer stem cells, developing a xenograft model, and studying the interaction of the immune system on these stem cells. Furthermore, the influence of the inflammatory milieu on the pathway of liver cancer stem cells to tumor development will also be studied.
3) Liver Microenvironment and Immunity. It is well established that the liver is an organ of relative immune privilege with respect to infectious disease, oral antigens, transplantation, and the formation of liver tumors. Since many liver tumors (hepatocellular carcinoma and cholangiocarcinoma) arise in a background of chronic inflammation or cirrhosis, we are also investigating the immune mechanisms that are unique to the liver. Experiments are being performed using immune cells (T cells, natural killer cells, and APCs) from human normal livers and cirrhotic or chronically inflamed livers to identify novel mechanisms of T cell priming/co-stimulation and regulation. The role of tissue resident macrophages (Kupffer cells) in these processes is also being explored. These mechanisms are also being rigorously tested in murine models of inflammation and tumor development to evaluate how the liver inflammatory milieu impacts on tumor development.