Liver cancer was the first cancer recognized as having a viral cause. Chronic inflammation resulting from infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) promote the development of liver tumors. CRI scientists have been studying liver cancer for more than three decades. In recent years, funding has gone to scientists who are working to understand the inflammation that is known to cause liver cancer.

• Gabriel A. Rabinovich, Ph.D., a CRI investigator from 2006-2010 at the University of Buenos Aires, Buenos Aires, Argentina, provided the first demonstration that galectin-1, a protein expressed by various normal and pathological tissues and that is thought to be a master regulator of certain immune responses, plays a role in modulating cell adhesion and tumor growth in liver cancer, suggesting that it could be a promising target to prevent or slow liver cancer progression.

• Paul Klenerman, M.D., Ph.D., a 2014-2016 Clinic and Laboratory Integration Program (CLIP) grantee and a professor at the University of Oxford, United Kingdom, is studying a novel set of immune cells called mucosal-associated invariant T (MAIT) cells and their association with inflammation as a cause of liver cancer. Klenerman proposes to investigate the ability of liver cancer to activate MAIT cells, as well as the ability of MAIT cells to recognize and kill liver cancer cells. The laboratory then aims to modulate the MAIT cells so that the recognition, targeting, and killing of liver cancer cells are improved. These studies will help us understand the mechanisms by which MAIT cells interact with liver tissue during cancer development, which could lead to the potential for an immunotherapy for liver cancer.

• In 2013, Thomas Chia Ting Fung, a graduate student at the University of Pennsylvania School of Medicine, was awarded a STaRT grant to study the role of innate lymphoid cell-controlled intestinal barrier function in hepatocellular carcinoma. Liver cancers commonly develop as a result of long-term, chronic liver injury due to viral infection or alcoholism. Many studies indicate that individuals with chronic liver disease not only exhibit impaired liver function but also damage to the intestinal wall, which is associated with excessive inflammation caused by the translocation of beneficial intestinal bacteria to the liver. These conditions are believed to accelerate the development and progression of liver cancer from chronic liver disease. Fung’s goal is to investigate how the immune system regulates intestinal damage and translocation of harmless bacteria during chronic liver injury and liver cancer development. These studies may identify novel and therapeutic targets for the prevention or treatment of liver cancer aimed at reducing intestinal bacteria-driven inflammation.

• More than 60% of adults in the United States are overweight or obese. Obesity is a risk factor for several cancers including and especially hepatocellular carcinoma (HCC), the dominant form of primary liver cancer. How immune homeostasis is maintained at a steady state in the liver and, more importantly, how such balance is breached by obesity remain poorly understood. Zhenyu Zhong, Ph.D., a 2014-2017 postdoctoral fellow at the University of California, San Diego, aims to identify the key regulator for maintaining immune homeostasis in the liver and delineating how obesity compromises immune homeostasis to drive inflammation and promote liver disease progression. This research will provide mechanistic insights into how obesity-induced liver damage and subsequent inflammation drive liver disease progression, and will likely promote the development of novel therapies for liver cancer.