Tumor-induced immune suppression.

肿瘤引起的免疫抑制。

基本信息

批准号：
7768386
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
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-20 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7768386
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 Disseminated Malignant Neoplasm Down-Regulation Excision Generations Genes Goals Immune Immunity Immunocompetent Immunologic Monitoring Immunologic Surveillance Immunosuppression 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 Transplantation Tumor Immunity cancer cell cancer immunotherapy cytokine gemcitabine improved inhibitor/antagonist macrophage neoplastic cell novel receptor success tumor tumor progression

项目摘要

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.

新型免疫疗法和癌症疫苗正在开发中，这些疗法取得了成功。需要有免疫功能的宿主免疫抑制发生在许多癌症患者中，并且是一个主要的原因。尽管有多种类型的癌症免疫疗法，但这是成功开发癌症免疫疗法的障碍。免疫抑制，肿瘤诱导的骨髓抑制细胞（MSC），也称为未成熟骨髓我们在许多患有移植性肿瘤和自发性肿瘤的患者和动物体内发现了细胞。最近在小鼠体内发现了一种基因，即信号转导器和转录激活剂 6 (STAT6) 基因，删除后，可大大提高已形成转移性乳腺的存活率和免疫排斥反应手术切除原发肿瘤后有效的肿瘤免疫癌。缺陷小鼠由三个成分介导：1) M1 型巨噬细胞的产生；2) 肿瘤特异性 CD8+ T 细胞的产生；3) MSC 水平迅速下降至基线。 MSC的积累和保留会抑制肿瘤特异性免疫并干扰主动免疫治疗，我们将检查 STATG 诱导荷瘤小鼠 MSC 保留的潜在机制。提出以下三个具体目标来实现这一目标： 1) 骨髓抑制细胞 (MSC) 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剂。鉴定导致 4T1 诱导的骨髓细胞术后保留的配体/受体组合 2）我们之前已经表明，IFNy对于MSC在术后快速消退是必需的。我们将确定导致这种退化的机制，并将对 STAT6 缺陷小鼠进行手术。阐明IFN^在此过程中的作用3)促炎细胞因子IL-1/?导致过量。我们将确定 IL-1 在术后小鼠中的积累和保留。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) 发现 MSC。在许多癌症患者中，它被认为是免疫监视和免疫治疗的障碍。使用吉西他滨（一种最近被证明可以下调 MSC 的药物），我们将确定是否 MSC 的减少/消除本身足以介导肿瘤排斥，如果消除 MSC 我们发现 MSC 会阻碍免疫监视，促进恶性细胞的生长，从而更好地了解肿瘤的调节。诱导的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。