Interleukin 10 and Breast Cancer Therapy

描述（由申请人提供）：我们之前已经表明

DESCRIPTION (provided by applicant): 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.