Interleukin 10 and Breast Cancer Therapy

描述（由申请人提供）：我们以前已经表明， 细胞因子白细胞介素10（IL-10）在小鼠模型中的过度表达 人乳腺癌抑制肿瘤生长和转移。这种治疗 免疫应答是免疫药物，需要T细胞和NK细胞。我们 已经表明重要的效应分子包括干扰素-γ（IFN-γ）， 一氧化氮和IFN-γ诱导的趋化因子Mig（单核因子诱导 干扰素-γ）和IP-10（诱导蛋白-10）。虽然高水平表达 IL-10在许多模型系统中显示出抗肿瘤活性， 数据还显示，IL-10是免疫抑制性的，并促进肿瘤生长， 一些模型。我们将测试假设，更高水平的IL-10，产生 在肿瘤发生的早期是治疗性的，而较低水平的IL-10， 随后在发展中的抗肿瘤反应将促进肿瘤生长。具体 目的1将研究IL-10表达的时间和定量方面， 疗法在生理条件下，IL-10表达下调IFN-γ， 通过CD 4 + T淋巴细胞的Th 1亚群表达。相反，IFN-γ是 在表达高水平IL-10的乳腺肿瘤中上调。具体目标2 将确定IL-10中IFN-γ和IFN-γ诱导型趋化因子的来源， 肿瘤回归模型我们已经确立了IFN-γ在免疫系统中的关键作用。 治疗反应，但不知道是否肿瘤细胞和宿主细胞 必须对IFN-γ有反应。具体目标3将鉴定IFN-γ的靶标。我们 已经表明趋化因子Mig和IP-10的上调有助于 IL-10介导的肿瘤抑制。这些趋化因子的特异性受体CXCR 3， 已经报道了肿瘤浸润淋巴细胞和NK细胞。我们有 在乳腺肿瘤细胞上检测到CXCR 3。具体目标4将决定作用 CXCR 3在肿瘤行为中的作用

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.