Spatially resolved analysis of the T cell immune contexture in lung cancer-associated brain metastases.
Spatially resolved analysis of the T cell immune contexture in lung cancer-associated brain metastases.
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DOI：
10.1136/jitc-2021-002684
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发表时间：
2021-10
影响因子：
10.9
通讯作者：
Goldberg SB
中科院分区：
文献类型：
--
作者：
Lu BY;Gupta R;Aguirre-Ducler A;Gianino N;Wyatt H;Ribeiro M;Chiang VL;Contessa JN;Adeniran AJ;Jilaveanu LB;Kluger HM;Schalper KA;Goldberg SB
尽管脑转移瘤 (BrM) 内存在独特的遗传改变和免疫学上独特的周围微环境，但 BrM 内肿瘤浸润淋巴细胞的组成和功能特性在很大程度上仍未被探索。特别是，BrMs 中共抑制受体的表达尚不清楚，例如程序性细胞死亡 1 (PD-1)、T 细胞免疫球蛋白粘蛋白受体 3 (TIM-3) 和淋巴细胞激活基因 3 (LAG-3)。本研究使用多重定量免疫荧光 (QIF) 评估 PD-L1 的局部表达、主要 T 细胞亚群的水平和功能概况，以及肺癌相关 BrM 和原发性肺肿瘤内的共抑制受体。 2002 年至 2015 年间 95 名肺癌患者的临床病理学注释样本以组织微阵列形式呈现。使用空间分辨和多重 QIF 来评估 PD-L1 蛋白、主要 T 细胞亚群的表型标记物（CD3、CD4、CD8 和 FOXP3）、细胞局部激活和增殖标记物（颗粒酶 B 和 Ki67）以及共抑制受体（PD-1、LAG-3 和 TIM-3）。在标记物选择的组织区室中测量每种标记物的信号，并研究标记物水平、肿瘤位置和主要临床病理变量之间的关联。总共分析了 41 个原发性肺肿瘤和 65 个 BrM，其中包括来自 11 名患者的配对样本。 BrM 和原发性肺肿瘤之间的肿瘤 PD-L1 表达水平相当。与原发性肺肿瘤相比，BrMs 的所有 T 细胞亚群水平均显着降低，并且 BrMs 中的 T 细胞显示出比原发性病变更低的颗粒酶 B 水平。 BrM 中 CD3+ T 细胞中的 PD-1、TIM-3 和 LAG-3 水平也显着降低。 BrMs 和原发性肺肿瘤配对样本患者的标记物表达显示出可比的结果。高 CD3+ T 细胞以及 CD3+ T 细胞中高水平的 TIM-3 和 LAG-3 与 BrM 的较长总生存期相关，但与原发性肺肿瘤无关。与原发性肺肿瘤相比，肺癌相关 BrM 显示出较低的 T 细胞浸润、溶细胞功能标志物和免疫调节信号。尽管存在这些差异，CD3+ T 细胞中高 TIM-3 和高 LAG-3 表达与更长的生存期相关。与原发性肺肿瘤相比，这些特征伴随着 PD-L1 蛋白表达水平相当。这些结果突出了大脑内肿瘤免疫微环境的独特方面，并为颅内聚焦治疗提供了进一步支持。
Despite unique genetic alterations within brain metastases (BrMs) and an immunologically distinct surrounding microenvironment, the composition and functional properties of tumor-infiltrating lymphocytes within BrM remain largely unexplored. In particular, the expression of coinhibitory receptors, such as programmed cell death 1 (PD-1), T cell immunoglobulin mucin receptor 3 (TIM-3), and lymphocyte activation gene 3 (LAG-3), within BrMs is unknown. Using multiplexed quantitative immunofluorescence (QIF), this study evaluates the localized expression of PD-L1, level and functional profile of major T cell subsets, and coinhibitory receptors within lung cancer-associated BrMs and primary lung tumors. Clinicopathologically annotated samples from 95 patients with lung cancer between 2002 and 2015 were represented in a tissue microarray format. Spatially resolved and multiplexed QIF was used to evaluate PD-L1 protein, phenotype markers for major T cell subsets (CD3, CD4, CD8, and FOXP3), cell-localized activation and proliferation markers (granzyme B and Ki67), and coinhibitory receptors (PD-1, LAG-3, and TIM-3). The signal for each marker was measured in marker-selected tissue compartments, and associations between marker levels, tumor location, and major clinicopathological variables were studied. In total, 41 primary lung tumors and 65 BrMs were analyzed, including paired samples from 11 patients. Levels of tumor PD-L1 expression were comparable between BrMs and primary lung tumors. BrMs had significantly lower levels of all T cell subsets relative to primary lung tumors, and T cells in BrMs displayed lower levels of granzyme B than primary lesions. PD-1, TIM-3, and LAG-3 levels in CD3+ T-cells were also significantly lower in BrMs. Marker expression in patients with paired samples from BrMs and primary lung tumors showed comparable results. High CD3+ T-cells, as well as high levels of TIM-3 and LAG-3 in CD3+ T-cells, were associated with longer overall survival in BrMs but not primary lung tumors. Lung cancer-associated BrMs display lower T cell infiltration, markers of cytolytic function, and immune regulatory signals than primary lung tumors. Despite these differences, high TIM-3 and high LAG-3 expressions in CD3+ T-cells were associated with longer survival. These features are accompanied by comparable levels of PD-L1 protein expression compared with primary lung tumors. These results highlight unique aspects of the tumor immune microenvironment within the brain and provide further support for intracranially focused therapies.
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影响因子：
51.1
作者：
Goldberg, Sarah B.;Schalper, Kurt A.;Kluger, Harriet M.
通讯作者：
Kluger, Harriet M.
DOI：
10.1016/j.bbrc.2018.03.053
发表时间：
2018-04-15
影响因子：
3.1
作者：
Zhou, Jie;Gong, Zhihua;Zhu, Bo
通讯作者：
Zhu, Bo
影响因子：
4.6
作者：
Mansfield AS;Ren H;Sutor S;Sarangi V;Nair A;Davila J;Elsbernd LR;Udell JB;Dronca RS;Park S;Markovic SN;Sun Z;Halling KC;Nevala WK;Aubry MC;Dong H;Jen J
通讯作者：
Jen J
影响因子：
--
作者：
Harter PN;Bernatz S;Scholz A;Zeiner PS;Zinke J;Kiyose M;Blasel S;Beschorner R;Senft C;Bender B;Ronellenfitsch MW;Wikman H;Glatzel M;Meinhardt M;Juratli TA;Steinbach JP;Plate KH;Wischhusen J;Weide B;Mittelbronn M
通讯作者：
Mittelbronn M
影响因子：
11.5
作者：
Datar, Ila;Sanmamed, Miguel F.;Schalper, Kurt A.
通讯作者：
Schalper, Kurt A.