Tumor-induced immune suppression

肿瘤诱导的免疫抑制

• 批准号: 7091016
• 负责人: SUZANNE OSTRAND-ROSENBERG
• 金额: $ 26.09万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-20 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7091016
• 关键词: apoptosis; blood cells; breast neoplasms; cellular oncology; cytotoxic T lymphocyte; gemcitabine; genetically modified animals; helper T lymphocyte; immunosuppression; inflammation; interferon gamma; interleukin 1; laboratory mouse; macrophage; mixed tissue /cell culture; neoplasm /cancer immunology; neoplasm /cancer surgery; neoplastic cell; prostaglandin E; prostaglandin receptor; receptor expression; transcription factor

DESCRIPTION (provided by applicant): Novel immunotherapies and cancer vaccines are being developed. The success of these therapies requires an immunocompetent host. Immune suppression occurs in many cancer patients and is a major impediment for developing successful cancer immunotherapies. Although there are numerous types of immune suppression, tumor-induced Myeloid Suppressor Cells (MSC), also known as Immature Myeloid Cells, are found in many patients and in animals with transplanted and spontaneous tumors. We have recently identified in mice a gene, the Signal Transducer and Activator of Transcription 6 (STAT6) gene, that when deleted, results in greatly improved survival and immune rejection of established metastatic mammary carcinoma following surgical removal of primary tumor. Effective tumor-immunity in post-surgery STAT6- deficient mice is mediated by three components: 1) The generation of M1 type macrophages; 2) The generation of tumor-specific CD8+ T cells; and 3) The rapid decrease to baseline in MSC levels. Because MSC accumulation and retention inhibit tumor-specific immunity and interfere with active immunotherapy, we will examine the mechanisms underlying STAT6-induced retention of MSC in tumor-bearing mice. We propose the following three Specific Aims to accomplish this goal: 1) Myeloid suppressor cells (MSC) are potent inhibitors of CD4+ and CD8+ T lymphocytes that effectively block tumor-specific immunity. We will identify the ligand/receptor combination responsible for the post-surgery retention of 4T1-induced myeloid suppressor cells. 2) We have previously shown that IFN? is required for the rapid regression of MSC in post- surgery STAT6-deficient mice. We will determine the mechanism responsible for this regression, and will clarify the role of IFN? in this process. 3) The pro-inflammatory cytokine IL-1? causes excessive accumulation and retention of MSC in post-surgery mice. We will determine how IL-1? regulates MSC levels, and ascertain if the link between inflammation and cancer is the induction of MSC. 4) MSC are found in many cancer patients and are thought to be an impediment to immune surveillance and immunotherapy. Using Gemcitabine, a drug that has recently been shown to down-regulate MSC, we will determine if reduction/elimination of MSC by itself is sufficient to mediate tumor rejection and if elimination of MSC impacts M1 macrophages and T lymphocytes. We have hypothesized that MSC block immunosurveillance, thereby facilitating the outgrowth of malignant cells. A better understanding of the regulation of tumor- induced immune suppression may reveal methods for controlling these cells in cancer patients, and thereby contribute to the development of effective cancer immunotherapies.

描述(申请人提供)：正在开发新的免疫疗法和癌症疫苗。这些疗法的成功需要有一个免疫能力强的宿主。免疫抑制存在于许多癌症患者中，是开发成功的癌症免疫疗法的主要障碍。虽然免疫抑制的类型很多，但肿瘤诱导的髓系抑制细胞(MSC)，也被称为未成熟的髓系细胞，在许多患者以及移植和自发肿瘤的动物中都被发现。我们最近在小鼠中发现了一种基因，信号转导和转录激活因子6(STAT6)基因，当该基因缺失时，可以极大地改善手术切除原发肿瘤后已建立的转移性乳腺癌的存活率和免疫排斥反应。STAT6基因缺陷小鼠术后有效的肿瘤免疫是由三个部分介导的：1)M1型巨噬细胞的产生；2)肿瘤特异性CD8+T细胞的产生；3)MSC水平迅速下降到基线水平。由于MSC的积聚和滞留抑制了肿瘤特异性免疫并干扰了主动免疫治疗，因此我们将研究STAT6在荷瘤小鼠中诱导MSC滞留的机制。为了实现这一目标，我们提出了以下三个具体目标：1)髓系抑制细胞(MSC)是有效阻断肿瘤特异性免疫的CD4+和CD8+T淋巴细胞的有效抑制物。我们将确定导致4T1诱导的髓系抑制细胞术后滞留的配体/受体组合。2)我们之前已经证明了干扰素？是STAT6基因缺陷小鼠术后MSC快速消退所必需的。我们将确定导致这种退化的机制，并澄清干扰素的作用？在这个过程中。3)促炎症细胞因子IL-1？导致术后小鼠体内MSC过度蓄积和滞留。我们将如何确定IL-1？调节MSC水平，并确定炎症和癌症之间的联系是否是MSC的诱导。4)在许多癌症患者中发现了MSC，并被认为是免疫监测和免疫治疗的障碍。使用吉西他滨，一种最近被证明下调MSC的药物，我们将确定MSC的减少/消除本身是否足以介导肿瘤排斥反应，以及MSC的消除是否影响M1巨噬细胞和T淋巴细胞。我们假设，MSC可以阻断免疫监视，从而促进恶性细胞的生长。更好地了解肿瘤诱导的免疫抑制的调节机制可能会揭示控制癌症患者这些细胞的方法，从而有助于开发有效的癌症免疫疗法。