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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA151414-03
Application #
8320341
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2010-09-13
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$174,960
Indirect Cost
$12,960
Name
University of Michigan Ann Arbor
Department
Surgery
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Yaqing; Yan, Wei; Mathew, Esha et al. (2014) CD4+ T lymphocyte ablation prevents pancreatic carcinogenesis in mice. Cancer Immunol Res 2:423-35
Welling, Theodore H; Feng, Mary; Wan, Shanshan et al. (2014) Neoadjuvant stereotactic body radiation therapy, capecitabine, and liver transplantation for unresectable hilar cholangiocarcinoma. Liver Transpl 20:81-8
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