Interleukin 10 and Breast Cancer Therapy

描述(由申请人提供)：我们以前已经证明 细胞因子白介素10(IL-10)在慢性阻塞性肺疾病小鼠模型中的过度表达 人类乳腺癌抑制肿瘤生长和转移。这是一种治疗 反应是免疫药物作用的，需要T细胞和NK细胞。我们 已经证明重要的效应分子包括干扰素-γ(干扰素-γ)， 一氧化氮和干扰素-γ诱导的趋化因子Mig(Monokine Induced 干扰素-γ)和IP-10(诱导蛋白-10)。虽然高水平的表达 现在已经在许多模型系统中显示出抗肿瘤活性，相互矛盾 数据还显示，IL-10具有免疫抑制作用，并促进肿瘤的生长 一些模特。我们将检验这一假设，即较高水平的IL-10产生 在肿瘤形成的早期是治疗性的，而较低水平的IL-10产生 在后期发展中的抗肿瘤反应会促进肿瘤的生长。特定的 目标1将检查IL-10在时间和数量方面的表达 心理治疗。在生理条件下，IL-10表达下调干扰素-γ CD4+T淋巴细胞Th1亚群的表达。相比之下，干扰素-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中干扰素-γ和干扰素-γ诱导的趋化因子的来源 肿瘤回归模型。我们已经确定了干扰素-γ在 治疗反应，但不知道肿瘤细胞和宿主细胞是否都 必须对干扰素-γ有反应。特异性靶点3将确定干扰素-γ的靶点。我们 已经表明，趋化因子Mig和IP-10的上调有助于 IL-10介导的肿瘤抑制作用。这些趋化因子的特异性受体，CXCR3， 已有关于肿瘤浸润性淋巴细胞和NK细胞的报道。我们有 检测乳腺肿瘤细胞表面CXCR3。具体目标4将决定角色 CXCR3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.