Tumor-induced immune suppression

描述（由申请人提供）：正在开发新的免疫疗法和癌症疫苗。这些疗法的成功需要具有免疫能力的宿主。免疫抑制发生在许多癌症患者中，是开发成功的癌症免疫疗法的主要障碍。尽管存在多种类型的免疫抑制，肿瘤诱导的髓系抑制细胞（MSC），也称为未成熟髓系细胞，在许多移植肿瘤和自发性肿瘤的患者和动物中发现。我们最近在小鼠中发现了一个基因，即信号传导和转录激活因子6 （STAT6）基因，当删除该基因时，在原发肿瘤手术切除后，可大大提高已建立的转移性乳腺癌的生存率和免疫排斥反应。STAT6-缺陷小鼠术后有效的肿瘤免疫是由三个因素介导的：1)M1型巨噬细胞的产生；2)肿瘤特异性CD8+ T细胞的生成；3) MSC水平迅速降至基线水平。由于间充质干细胞的积累和滞留会抑制肿瘤特异性免疫并干扰主动免疫治疗，我们将研究stat6诱导的荷瘤小鼠间充质干细胞滞留的机制。我们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）是CD4+和CD8+ T淋巴细胞的有效抑制剂，可有效阻断肿瘤特异性免疫。我们将确定4t1诱导的骨髓抑制细胞术后保留的配体/受体组合。2)我们之前已经证明IFN？是术后stat6缺失小鼠骨髓间充质干细胞快速消退所必需的。我们将确定导致这种回归的机制，并阐明IFN的作用。在这个过程中。3)促炎细胞因子IL-1？导致术后小鼠骨髓间充质干细胞过度积累和滞留。我们会确定IL-1？调节MSC水平，并确定炎症和癌症之间的联系是否与MSC的诱导有关。4)在许多癌症患者中发现MSC，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MSC本身的减少/消除是否足以介导肿瘤排斥，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控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。

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.