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Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma.

肿瘤微环境中的免疫细胞构成可预测弥漫性大 B 细胞淋巴瘤的结局。

  • 影响因子:4.07
  • DOI:10.3324/haematol.2019.243626
  • 作者列表:"Autio M","Leivonen SK","Brück O","Mustjoki S","Jørgensen JM","Karjalainen-Lindsberg ML","Beiske K","Holte H","Pellinen T","Leppä S
  • 发表时间:2020-02-20
Abstract

:Tumor microenvironment (TME) and limited immune surveillance play important roles in lymphoma pathogenesis. Here, we aimed to characterize immunological profiles of diffuse large B-cell lymphoma (DLBCL), and predict the outcome in response to immunochemotherapy. We profiled the expression of 730 immune-related genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize T-cell phenotypes, including cytotoxic T-cells (CD8, Granzyme B, OX40, Ki67), T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188 patients. We observed a high degree of heterogeneity at the transcriptome level. Correlation matrix analysis identified gene expression signatures with highly correlating genes - the main cluster containing genes for cytolytic factors, immune checkpoint molecules, T-cells and macrophages, together entitled as a TME immune cell signature. Immunophenotyping of the distinct cell subsets revealed that a high proportion of immune checkpoint positive T-cells translated to unfavorable survival. Together, our results demonstrate that the immunological profile of DLBCL TME is heterogeneous and clinically meaningful. This highlights the potential impact of T-cell immune checkpoint in regulating survival and resistance to immunochemotherapy.

摘要

: 肿瘤微环境 (TME) 和有限免疫监视在淋巴瘤发病机制中起重要作用。在此,我们旨在描述弥漫性大 B 细胞淋巴瘤 (DLBCL) 的免疫学特征,并预测免疫化疗的结局。我们利用 Nanostring 平台分析了 81 例 DLBCL 患者肿瘤组织中 730 个免疫相关基因的表达,并使用多重免疫组化来表征 T 细胞表型, 包括细胞毒性 T 细胞 (CD8 、颗粒酶 B 、 OX40 、 Ki67) 、 T 细胞免疫检查点 (CD3 、 CD4 、 CD8 、 PD1 、 TIM3 、 LAG3) 、以及 188 例患者的调节性 T 细胞和 Th1 效应细胞 (CD3 、 CD4 、 FOXP3 、 TBET)。我们在转录组水平观察到高度异质性。相关矩阵分析确定了具有高度相关基因的基因表达标签 -- 主要包含细胞溶解因子、免疫检查点分子、 T 细胞和巨噬细胞的基因簇,共同命名为 TME 免疫细胞标签。不同细胞亚群的免疫表型发现,高比例的免疫检查点阳性 T 细胞转化为不利的存活。总之,我们的结果证明 DLBCL TME 的免疫学特征是异质性的,具有临床意义。这突出了 T 细胞免疫检查点在调节生存和免疫化疗抵抗中的潜在影响。

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