Biomarkers of the Proinflammatory Response and Elements of Immune Suppression

项目1建立在我们的初步数据和最近的文献报道的基础上，这些文献已经确定了一系列在肿瘤组织和循环血液中的促炎免疫反应和免疫抑制的生物标志物，这些生物标志物对接受免疫治疗的黑色素瘤患者具有良好的治疗预测和疾病预后价值。这些将作为E1609试验的一部分同时进行评估，在可手术的IIIB/C期和M1a/b期黑色素瘤患者中测试大剂量和标准剂量的辅助剂ipilimumab与干扰素。该项目将有3个目标在每个E1609试验队列中进行测试： 目标1：循环。(1a)循环细胞群：测试基线和/或治疗早期IFNG+CD4+和IFNG+CD8+抗原特异性T细胞免疫以及特定宿主抑制元件(定义的调节性T细胞和髓系来源的抑制细胞群)与临床结果(RF和OS)相关的假设，(1b)循环血清生物标志物：测试基线和/或治疗早期促炎细胞因子和趋化因子特征与临床结果相关的假设。 目的2：肿瘤与肿瘤微环境：首先，验证治疗前、促炎、肿瘤微环境(免疫相关基因的高表达水平)与临床预后(RFS和OS)相关的假设。作为次级目标，我们将测试肿瘤突变状态(BRAF、NRAS和野生型状态)与临床结果的相关性。我们还将评估免疫相关基因甲基化水平的预测价值。 目的3：基于公共系统生物学，将开发一个整体模型分析来连接AIMS 1和2中感兴趣的标记物(将循环中的显著标记物与肿瘤微环境中的那些标记物联系起来)，其中我们假设将在每个试验臂内识别和验证生物标记物的促炎治疗预测标记(S)。基于共同的系统生物学，我们期望针对ipilimumab和hdi的重叠预测模型。

Project 1 builds on our preliminary data and recent reports in the literature that have identified a series of biomarkers of a pro-inflammatory immune response and of immunosuppression in both tumor tissue and in circulating blood that have promising therapeutic predictive and disease prognostic value in melanoma patients treated with Immunotherapy. These will be simultaneously evaluated as part of E1609 trial testing adjuvant ipilimumab at high dose and standard dose versus IFN¿ in patients with operable stage IIIB/C and M1a/b melanoma. This project will have 3 aims to be tested within each of the E1609 trial cohorts: Aim 1: Circulation. (1a) Circulating cellular populations: test the hypothesis that baseline and/or early on-treatment IFNg+CD4+ and IFNg+CD8+ antigen specific T-cell immunity as well as specific host suppressor elements (defined populations of regulatory T cells and myeloid-derived suppressor cells) correlate with clinical outcome (RFS and OS), (1b) Circulating serum biomarkers: test the hypothesis that baseline and/or early on-treatment pro-inflammatory cytokine and chemokine profiles correlate with clinical outcome. Aim 2: Tumor and tumor microenvironment: First, test the hypothesis that a pretreatment, pro-inflammatory, tumor microenvironment (high baseline expression levels of immune-related genes) correlates with clinical outcome (RFS and OS). As secondary sub-aims, we will test the association of the tumor mutational status (BRAF, NRAS and wild-type status for both) and clinical outcome. We will also assess the predictive value of the methylation levels of immune-related genes. Aim 3: Based on the common systems biology, an overall model analysis will be developed to link markers of interest in Aims 1 and 2 (linking significant markers in the circulation with those in the tumor microenvironment) where we hypothesize that a pro-inflammatory therapeutically predictive signature(s) of biomarkers will be identified and validated within each of the trial arms. We expect overlapping predictive models for ipilimumab and HDI based on the common systems biology.