We have shown previously that overexpression of the cytokine Interleukin 10 (IL-10) in a murine model of human breast cancer inhibits tumor growth and metastasis. This therapeutic response is immunologically medicated and requires T cells and NK cells. We have shown that important effector molecules include interferon-y (IFN-y), nitric oxide, and the IFN-y-inducible chemokines Mig (monokine induce interferon-y) and IP-10 (inducible protein-10). Although high level expression of IL-10 has now shown antitumor activity in many model systems, conflicting data also reveals that IL-10 is immunosuppressive and promotes tumor growth in some models. We will test the hypothesis that higher levels of IL-10, produced early in tumorigenesis are therapeutic, whereas lower levels of IL-10, produced later in the developing antitumor response will promote tumor growth.
Specific Aim 1 will examine temporal and quantitative aspects of IL-10 expression in therapy. Under physiologic conditions, IL-10 expression downregulates IFN-y expression by the Th1 subset of CD4+ T lymphocytes. In contrast, IFN-y is upregulated in mammary tumors expressing high levels of IL-10.
Specific Aim 2 will identify the source of IFN-y and IFN-y-inducible chemokines in the IL-10 tumor regression model. We have established a critical role for IFN-y in the therapeutic response, but do not know if both the tumor cell and host cells must respond to IFN-y.
Specific Aim 3 will identify the target of IFN-y. We have shown that upregulation of the chemokines Mig and IP-10 contributes to IL-10 mediated tumor inhibition. Specific receptor for these chemokines, CXCR3, has been reported on tumor-infiltrating lymphocytes and NK cells. We have detected CXCR3 on mammary tumor cells.
Specific Aim 4 will determine the role of CXCR3 in tumor behavior.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-ET-1 (02))
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Hecht, Toby T
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University of Maryland Baltimore
Schools of Medicine
United States
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Walser, Tonya C; Ma, Xinrong; Kundu, Namita et al. (2007) Immune-mediated modulation of breast cancer growth and metastasis by the chemokine Mig (CXCL9) in a murine model. J Immunother 30:490-8
Walser, Tonya C; Rifat, Salah; Ma, Xinrong et al. (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res 66:7701-7
Dorsey, Russell; Kundu, Namita; Yang, Qingyuan et al. (2002) Immunotherapy with interleukin-10 depends on the CXC chemokines inducible protein-10 and monokine induced by IFN-gamma. Cancer Res 62:2606-10
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