Tumor-induced immune suppression.

新的免疫疗法和癌症疫苗正在开发中。这些疗法的成功 需要有免疫活性的宿主免疫抑制发生在许多癌症患者中，并且是一种主要的癌症。 阻碍了癌症免疫疗法的成功发展。虽然有许多类型的 免疫抑制，肿瘤诱导的骨髓抑制细胞（MSC），也称为未成熟骨髓 在许多患有移植性和自发性肿瘤的患者和动物中发现了细胞。我们有 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（STAT 6）基因， 当删除时，导致建立的转移性乳腺癌的存活和免疫排斥大大改善， 手术切除原发肿瘤后的癌症。术后STAT 6的有效肿瘤免疫- 缺陷型小鼠由三种成分介导：1）M1型巨噬细胞的产生; 2） 肿瘤特异性CD 8 + T细胞的产生;和3）MSC水平快速降低至基线。因为 MSC积聚和滞留抑制肿瘤特异性免疫并干扰主动免疫治疗，我们 将研究STATG诱导的MSC在荷瘤小鼠中滞留的机制。我们 我提出了以下三个具体目标来实现这一目标：1）骨髓抑制细胞（MSC）是 有效阻断肿瘤特异性免疫的CD 4+和CD 8 + T淋巴细胞的强效抑制剂。我们将 确定负责4 T1诱导的髓系细胞术后保留的配体/受体组合 抑制细胞2)我们以前已经表明，IFN γ是MSC在术后快速消退所必需的。 STAT 6缺陷小鼠的手术。我们将确定造成这种倒退的机制，并将 阐明IFN γ在此过程中的作用。3)促炎细胞因子IL-1/？导致过度 MSC在手术后小鼠中的积累和保留。我们将确定IL-1是如何调节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，并且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自身的减少/消除足以介导肿瘤排斥，并且如果MSC的消除 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。更好地理解肿瘤的调节- 诱导的免疫抑制可能揭示了控制癌症患者中这些细胞的方法， 有助于开发有效的癌症免疫疗法。

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.