Tumor-induced immune suppression.

肿瘤引起的免疫抑制。

• 批准号: 7364200
• 负责人: SUZANNE OSTRAND-ROSENBERG
• 金额: $ 25.34万
• 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/7364200
• 关键词: Active Immunotherapy; Animals; Apoptosis; Breast Adenocarcinoma; Breast Carcinoma; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cancer Vaccines; Cells; Data; Development; Dinoprostone; Disease; Disease regression; Disseminated Malignant Neoplasm; Down-Regulation; Excision; Generations; Genes; Goals; Immune; Immunity; Immunocompetent; Immunologic Monitoring; Immunologic Surveillance; Immunotherapy; Inflammation; Inflammatory; Interferons; Interleukin-1; Ligands; Link; Malignant Neoplasms; Mediating; Metastatic to; Methods; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Preparations; Primary Neoplasm; Process; Regulation; Resistance; Role; STAT6 Transcription Factor; Signal Transduction; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Thinking; Transplantation; Tumor Immunity; Tumor Suppression; cancer cell; cancer immunotherapy; cytokine; gemcitabine; improved; inhibitor/antagonist; macrophage; neoplastic cell; novel; receptor; success; tumor; tumor progression

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 STATG-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 IFNy 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.

新的免疫疗法和癌症疫苗正在开发中。这些疗法的成功 需要免疫能力强的宿主。免疫抑制发生在许多癌症患者中，是一种主要的 开发成功的癌症免疫疗法的障碍。尽管有许多类型的 免疫抑制，肿瘤诱导的髓系抑制细胞(MSC)，也称为未成熟髓系 细胞，在许多患者以及移植和自发性肿瘤的动物身上都能发现。我们有 最近在小鼠身上发现了一种基因，信号转导和转录激活因子6(STAT6)基因，它可以 删除后，可显著提高已建立的转移性乳腺的存活率和免疫排斥反应 外科手术切除原发肿瘤后的癌症。手术后有效的肿瘤免疫状态6- 缺陷小鼠由三个部分介导：1)M1型巨噬细胞的产生；2) 肿瘤特异性CD8+T细胞的产生；以及3)MSC水平迅速下降到基线水平。因为 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 将研究STATG诱导MSC在荷瘤小鼠中滞留的机制。我们 为实现这一目标，提出了以下三个具体目标：1)骨髓抑制细胞 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。我们会 确定4T1诱导的髓系细胞术后滞留的配体/受体组合 抑制细胞。2)我们先前已经证明，IFNY是MSC在术后快速回归所必需的。 手术STAT6缺陷小鼠。我们将确定造成这种倒退的机制，并将 阐明干扰素在这一过程中的作用。3)促炎症细胞因子IL-1/？导致过度 骨髓间充质干细胞在术后小鼠体内的蓄积和滞留。我们将确定IL-1是如何调节MSC的 水平，并确定炎症和癌症之间的联系是否是诱导MSC。4)发现了MSC 在许多癌症患者中，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，我们将确定是否 MSC的减少/消除本身就足以介导肿瘤排斥反应，如果消除MSC 影响M1巨噬细胞和T淋巴细胞。我们假设骨髓间充质干细胞可以阻断免疫监视， 从而促进了恶性细胞的生长。更好地理解肿瘤的调节-- 诱导免疫抑制可能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。