Recent advances have highlighted an important role for chronic inflammation in promoting tumor development. How chronic inflammation promotes tumor formation during the early stages of tumorigenesis remains unknown. In the preliminary studies, we investigated whether MyD88, a common adaptor for the innate immune signaling pathways, plays a role in the development of inflammation-induced, spontaneously developed hepatocellular carcinoma (HCC). We showed that hepatocyte-intrinsic MyD88 signaling is critical for the development of the precancerous dysplastic nodules and their progression to HCC. The objective of this application is to elucidate critical mechanisms governing the immune evasion by precancerous dysplastic lesions, leading to progression to HCC. Specifically, we hypothesize that precancerous dysplastic hepatocytes evade immune elimination by recruiting immunosuppressive inflammatory monocytes. We will test this hypothesis and pursue the critical tumor-derived factors involved in the recruitment of the immune suppressors. By providing how tumor-derived factors influence the anti-tumor immune response during the early time points of tumorigenesis, these studies will have profound implications in the development of new therapeutic targets for cancer prevention and therapy.

Public Health Relevance

Chronic inflammation has been implicated in cancer progression. How the presence of chronic inflammation promotes cancer remains largely unknown. The proposed work will identify critical factors mediating the inflammation-associated cancer, and in turn will help us design more effective strategies for treating cancer as well as preventing relapses. Thus, it is highly cancer-relevant.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-RTRB-Z (M2))
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Howcroft, Thomas K
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Brennan, Todd V; Yang, Yiping (2017) PD-L1 serves as a double agent in separating GVL from GVHD. J Clin Invest 127:1627-1630
Yuan, Yuqing; Yang, Yiping; Huang, Xiaopei (2017) IL-21 is required for CD4 memory formation in response to viral infection. JCI Insight 2:e90652
Petty, Amy J; Yang, Yiping (2017) Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy 9:289-302
Brandstadter, Joshua D; Chen, Huiyao; Jiang, Songfu et al. (2017) IL-18-dependent NKG2D ligand upregulation on accessory cells is mediated by the PI3K/GSK-3 pathway. J Leukoc Biol 101:1317-1323
Fortin, Carl; Yang, Yiping; Huang, Xiaopei (2017) Monocytic myeloid-derived suppressor cells regulate T-cell responses against vaccinia virus. Eur J Immunol 47:1022-1031
Zhu, Jiangao; Chen, Huiyao; Huang, Xiaopei et al. (2016) Ly6Chi monocytes regulate T cell responses in viral hepatitis. JCI Insight 1:e89880
Heyman, Benjamin; Yang, Yiping (2016) Mechanisms of heparanase inhibitors in cancer therapy. Exp Hematol 44:1002-1012
Huang, Xiaopei; Yang, Yiping (2016) Driving an improved CAR for cancer immunotherapy. J Clin Invest 126:2795-8
Yang, Yiping (2015) Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 125:3335-7