Transplant Translational Research Program
Our laboratory uses a combination of clinical data and patient-derived specimens to study how HCC and cirrhosis influence key immune populations which can block immune response directed tumors.
Chronic viral infection (Hepatitis B/C) and fatty liver disease caused by chronic alcohol use and/or metabolic disease are the major causes of inflammation in the liver. Chronic liver inflammation, or hepatitis, leads to cirrhosis which is characterized by immune cell infiltration, liver injury, and fibrotic changes ultimately leading to liver failure. The constant cycle of inflammation, liver injury, and repair during cirrhosis dramatically increase the risk of develop liver cancer, or hepatocellular carcinoma (HCC). If diagnosed at an early stage, liver transplantation is the best treatment option for cirrhotic patients with HCC, as transplantation removes not only the cancer but also underlying liver disease which led to HCC. Unfortunately, HCC is a very aggressive cancer which can rapidly metastasize to other tissues if left untreated. Many patients who receive liver transplants for HCC experience tumor recurrence within 3 to 5 years after transplantation. HCC recurs because of tumor cells which escape the primary tumor site, where they can survive undetectable in the circulation or as small micro-metastases outside the liver.
Current research in our laboratory is focused on the following projects and are based around a 3-yr ongoing prospective study of waitlist HCC patients being bridged to liver transplantation:
(1) Immunomodulatory role of unconjugated bilirubin on effector T cell : dendritic cell interactions. We study how elevated bilirubin (hyperbilirubinemia) influence the behavior of lymphocytes (T cells) and dendritic cells, two of the critical immune populations involved in the immune response against tumors. The role of bilirubin in promoting regulatory T cell survival and immune suppression as well as interfering with dendritic cell maturation and function are key components of this study. Using T cell receptor sequencing, we are studying how bilirubin effects anti-tumor T cell repertoire following locoregional therapy. Our goal is to identify strategies to circumvent the effects of bilirubin on the immune system to increase the success of tumor-directed therapy in HCC patients being bridged to liver transplantation.
(2) Implementation of the AFP, AFP-L3, and DCP HCC biomarker panel as a prognostic index of locoregional therapy response and transplant outcomes. In this study, we prospectively tracking biomarker values from treatment naïve presentation, through liver transplantation and transplant follow-up. The goal of these studies is to determine the utility of the biomarker panel as an index of tumor biological aggressiveness and potential resistance to tumor-directed therapy. Further, we are tracking biomarker expression after transplantation to determine if the panel can be utilized in HCC surveillance as an early indicator of tumor recurrence.
(3) Intention-to-treat analysis of liver transplant waitlist HCC patients to identify prognostic immune profiles associated with favorable treatment outcomes and post-transplant recurrence rates. Using a single-center database originating in 2012, our group maintains trends for all patients who underwent transplant evaluation and HCC treatment with the goal of curative liver transplantation. Using this database and the corresponding specimen biobank, we probe for tumor oncogene profiles, tolerogenic immune population expansion, and shifts in liver reserve function to identify interventional approaches which may direct interventional radiology approaches and treatment algorithms to improve tumor response rates and limit/eradicate tumor burden prior to liver transplantation.