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A Th1/IFNγ Gene Signature Is Prognostic in the Adjuvant Setting of Resectable High-Risk Melanoma but Not in Non-Small Cell Lung Cancer.

Th1/ifn γ 基因标记在可切除高危黑色素瘤的辅助治疗中是预后的,但在非小细胞肺癌中不是。

  • 影响因子:8.32
  • DOI:10.1158/1078-0432.CCR-18-3717
  • 作者列表:"Dizier B","Callegaro A","Debois M","Dreno B","Hersey P","Gogas HJ","Kirkwood JM","Vansteenkiste JF","Sequist LV","Atanackovic D","Goeman J","van Houwelingen H","Salceda S","Wang F","Therasse P","Debruyne C","Spiessens B","Brichard VG","Louahed J","Ulloa-Montoya F
  • 发表时间:2020-04-01
Abstract

PURPOSE:Immune components of the tumor microenvironment (TME) have been associated with disease outcome. We prospectively evaluated the association of an immune-related gene signature (GS) with clinical outcome in melanoma and non-small cell lung cancer (NSCLC) tumor samples from two phase III studies. EXPERIMENTAL DESIGN:The GS was prospectively validated using an adaptive signature design to optimize it for the sample type and technology used in phase III studies. One-third of the samples were used as "training set"; the remaining two thirds, constituting the "test set," were used for the prospective validation of the GS. RESULTS:In the melanoma training set, the expression level of eight Th1/IFNγ-related genes in tumor-positive lymph node tissue predicted the duration of disease-free survival (DFS) and overall survival (OS) in the placebo arm. This GS was prospectively and independently validated as prognostic in the test set. Building a multivariate Cox model in the test set placebo patients from clinical covariates and the GS score, an increased number of melanoma-involved lymph nodes and the GS were associated with DFS and OS. This GS was not associated with DFS in NSCLC, although expression of the Th1/IFNγ-related genes was associated with the presence of lymphocytes in tumor samples in both indications. CONCLUSIONS:These findings provide evidence that expression of Th1/IFNγ genes in the TME, as measured by this GS, is associated with clinical outcome in melanoma. This suggests that, using this GS, patients with stage IIIB/C melanoma can be classified into different risk groups.

摘要

目的: 肿瘤微环境 (TME) 的免疫成分与疾病结局相关。我们前瞻性评估了两项 III 期研究的黑色素瘤和非小细胞肺癌 (NSCLC) 肿瘤样本中免疫相关基因标记 (GS) 与临床结局的相关性。 实验设计: 使用自适应签名设计对 GS 进行前瞻性验证,以优化其用于 III 期研究的样本类型和技术。三分之一的样本用作 “训练集”; 其余 3分之2,构成 “测试集”,用于 GS 的前瞻性验证。 结果: 在黑色素瘤训练集中,肿瘤阳性淋巴结组织中 8 个 Th1/ifn γ 相关基因的表达水平预测无病生存期 (DFS) 的持续时间和安慰剂组的总生存期 (OS)。该 GS 在测试集中被前瞻性独立验证为预后。从临床协变量和 GS 评分构建测试集中安慰剂患者的多变量 Cox 模型,黑色素瘤受累淋巴结数量增加,GS 与 DFS 和 OS 相关。该 GS 与 NSCLC 的 DFS 无关,尽管 Th1/ifn γ 相关基因的表达与两种适应症的肿瘤样本中淋巴细胞的存在相关。 结论: 这些发现提供了 TME 中 Th1/ifn γ 基因表达的证据,通过该 GS 测量,与黑色素瘤的临床结局相关。这表明,使用该 GS,IIIB/C 期黑色素瘤患者可以分为不同的风险组。

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DOI:10.1002/ijc.32847
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翻译标题与摘要 下载文献
影响因子:4.88
发表时间:2020-03-01
DOI:10.1016/j.ecoenv.2019.110098
作者列表:["Suvina V","Kokulnathan T","Wang TJ","Balakrishna RG"]

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影响因子:6.50
发表时间:2020-03-31
来源期刊:Cancer letters
DOI:10.1016/j.canlet.2019.12.039
作者列表:["Zhou Z","Zhou Q","Wu X","Xu S","Hu X","Tao X","Li B","Peng J","Li D","Shen L","Cao Y","Yang L"]

METHODS::Several studies have indicated that cancer-associated fibroblasts (CAFs) could promote cancer progression in many malignancies. However, the mechanism by which CAFs promote the growth and metastasis of lung cancer remains poorly defined. In the present study, CAFs and normal fibroblasts (NFs) were isolated from human lung cancer and adjacent tissue. The data showed that the conditional medium (CM) of CAFs could increase the proliferation, migration and invasion of lung cancer cells. Vascular cell adhesion molecule-1 (VCAM-1) showed a higher expression in CAF-CM than NF-CM, and blocking VCAM-1 in CAF-CM attenuated the proliferation and invasion of cancer cells. Further, the results showed that VCAM-1 secreted from CAFs activated AKT and MAPK signaling via receptor α4β1 integrin (very-late antigen (VLA)-4) in lung cancer cells. Moreover, CAFs promoted VCAM-1 expression and tumor growth in vivo. Additionally, bioinformatics analysis indicated a positive correlation on the CAF marker protein alpha-smooth muscle actin (α-SMA) and VCAM-1 expression, which was associated with a poor prognosis in lung cancer patients. These findings demonstrate that the VCAM-1 secreted from CAFs enhances growth and invasion by activating the AKT and MAPK signaling of lung cancer cells.

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