This project utilizes a novel murine model to study immune processes that influence metastasis of intraocular melanoma. Intraocular melanoma (uveal melanoma) is the most common intraocular tumor in adults and has an incidence of 7 cases per million adults per year in the Caucasian population. Up to 50% of the uveal melanoma patients die from metastatic disease with the liver being the organ most frequently affected. Approximately 90% of patients who die from uveal melanoma have liver metastases at the time of death. Unfortunately, the long-term survival of uveal melanoma patients has not improved in over 35 years and to date there is no effective therapy for liver metastases of uveal melanoma. A compelling body of evidence suggests that elements of the innate immune system, namely natural killer (NK) cells, have an important impact on the development of liver metastasis and mortality in uveal melanoma patients. Recent findings from our laboratory have shown that liver metastases arising from intraocular melanomas induce NKT cells in the liver to suppress the anti-metastatic function of hepatic NK cells. Accordingly, Specific Aim #1 will characterize the molecules and mechanisms by which liver NKT cells suppress NK cell-mediated resistance to liver metastases of intraocular melanomas. Preliminary results from other experiments strongly suggest that neutrophils contribute to the resistance to the metastasis of intraocular melanomas, possibly by activating NK cells. The novel role neutrophils in contributing to the resistance to ocular tumor metastases will be explored. Other investigations in Specific Aim #1 will test strategies for reversing NKT cell-mediated suppression of NK cells and thereby reducing metastatic disease in intraocular-bearing hosts. Uveal melanoma, like most cancers, is a disease of aging with 61 years being the median age for uveal melanoma patients. Preliminary studies indicate that aging mice have more severe liver metastases than young mice and that this exacerbation of metastatic disease is reversed by depleting tumor-infiltrating macrophages. With this in mind, Specific Aim #2 will examine the role of aging on metastases arising from intraocular melanomas and develop strategies for restoring the aging host's resistance to metastatic disease.

Public Health Relevance

Uveal melanoma is the most common intraocular cancer in adults with approximately 50% of uveal melanoma patients dying from metastases to the liver. Currently there is no effective treatment for liver metastases of uveal melanoma and the five-year survival rate has not changed in over 30 years. This project explores methods for activating a specific component of the immune system called natural killer cells to combat liver metastases arising from uveal melanomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA030276-32
Application #
8613438
Study Section
Special Emphasis Panel (ZRG1-BDCN-G (02))
Program Officer
Yovandich, Jason L
Project Start
1981-07-01
Project End
2017-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
32
Fiscal Year
2014
Total Cost
$253,954
Indirect Cost
$94,234
Name
University of Texas Sw Medical Center Dallas
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Li, Haochuan; Niederkorn, Jerry Y; Sadegh, Leila et al. (2013) Epigenetic regulation of CXCR4 expression by the ocular microenvironment. Invest Ophthalmol Vis Sci 54:234-43
Yang, Wanhua; Li, Haochuan; Mayhew, Elizabeth et al. (2011) NKT cell exacerbation of liver metastases arising from melanomas transplanted into either the eyes or spleens of mice. Invest Ophthalmol Vis Sci 52:3094-102
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Niederkorn, Jerry Y (2009) Immune escape mechanisms of intraocular tumors. Prog Retin Eye Res 28:329-47
Li, Haochuan; Yang, Wanhua; Chen, Peter W et al. (2009) Inhibition of chemokine receptor expression on uveal melanomas by CXCR4 siRNA and its effect on uveal melanoma liver metastases. Invest Ophthalmol Vis Sci 50:5522-8
Li, Haochuan; Alizadeh, Hassan; Niederkorn, Jerry Y (2008) Differential expression of chemokine receptors on uveal melanoma cells and their metastases. Invest Ophthalmol Vis Sci 49:636-43
Yang, Wanhua; Chen, Peter W; Li, Haochuan et al. (2008) PD-L1: PD-1 interaction contributes to the functional suppression of T-cell responses to human uveal melanoma cells in vitro. Invest Ophthalmol Vis Sci 49:2518-25
Chen, Peter W; Mellon, Jessamee K; Mayhew, Elizabeth et al. (2007) Uveal melanoma expression of indoleamine 2,3-deoxygenase: establishment of an immune privileged environment by tryptophan depletion. Exp Eye Res 85:617-25
Li, Haochuan; Niederkorn, Jerry Y; Neelam, Sudha et al. (2006) Downregulation of survivin expression enhances sensitivity of cultured uveal melanoma cells to cisplatin treatment. Exp Eye Res 83:176-82

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