Hepatocellular carcinoma (HCC) is the second leading cause of cancer deaths worldwide. Tumor immune effector and suppressive responses have been linked to improved and poorer clinical responses, respectively. Preliminary data in this proposal demonstrates that hepatic antigen presenting cells (APC) expressing inhibitory B7 family members contribute to the immune suppressive network in human HCC. The long term goal of this project is to define the HCC immune suppressive network and its contribution to HCC progression as well as its therapeutic implications. In addition, biological insight into the function of resident APC subsets within the human liver and interaction with other T cell subsets will translate knowledge to other disease states such as chronic viral hepatitis, autoimmune hepatitis, and transplantation. The overarching hypothesis for this project is that HCC tumor factors promote or recruit inhibitory APC subsets that control the immune suppressive network utilizing inhibitory B7 family member function. This proposal will integrate data obtained from human HCC tissues, peripheral blood, clinical data from HCC patients, and murine models of HCC. The nature of APC subsets, relevance of B7 family members, and mechanisms of their actions in the immune suppressive network will be explored.

Public Health Relevance

The treatment options for HCC are limited and there is currently only one known medical therapy for HCC. Immune regulation is increasingly being recognized to occur in the tumor microenvironment and contributes directly to tumor immunopathogenesis. However, the cellular and molecular mechanisms that render an immune suppressive network in HCC are incompletely understood. This proposal is devoted to defining the nature and functionality of these newly described B7 family members and the unique biology of APCs, T cells, and NK cells within the human liver and HCC. A further understanding of these dynamic processes will allow for future development of targeted immunotherapies for HCC as well as a better understanding of how best to tailor current therapies and surveillance programs to patients at risk for developing HCC. Research Relevance The treatment options for HCC are limited and there is currently only one known medical therapy for HCC. Immune regulation is increasingly being recognized to occur in the tumor microenvironment and contributes directly to tumor immunopathogenesis. However, the cellular and molecular mechanisms that render an immune suppressive network in HCC are incompletely understood. This proposal is devoted to defining the nature and functionality of these newly described B7 family members and the unique biology of APCs, T cells, and NK cells within the human liver and HCC. A further understanding of these dynamic processes will allow for future development of targeted immunotherapies for HCC as well as a better understanding of how best to tailor current therapies and surveillance programs to patients at risk for developing HCC.

Agency
National Institute of Health (NIH)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA151414-05
Application #
8717405
Study Section
Subcommittee B - Comprehensiveness (NCI)
Program Officer
Lim, Susan E
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Wan, Shanshan; Zhao, Ende; Kryczek, Ilona et al. (2014) Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147:1393-404