Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non-small cell lung cancer.
Tumor cellular proliferation is associated with enhanced immune checkpoint expression in stage I non-small cell lung cancer.
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DOI：
10.1016/j.jtcvs.2019.04.084
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发表时间：
2019-09
期刊：
影响因子：
--
通讯作者：
MD Anderson Lung Cancer Immune Microenvironment Working Group
中科院分区：
文献类型：
--
作者：
Mitchell KG;Parra ER;Nelson DB;Zhang J;Wistuba II;Fujimoto J;Roth JA;Antonoff MB;MD Anderson Lung Cancer Immune Microenvironment Working Group
Ki 67是肿瘤增殖活性的标志物，已知在多种实体恶性肿瘤中具有预后意义。我们试图描述切除的非小细胞肺癌患者中Ki 67表达、免疫细胞浸润和免疫检查点表达之间的关系。使用组织微阵列分析了接受I至III期非小细胞肺癌切除术的患者的标本（1997-2012年）。恶性指数定量为表达Ki 67的恶性细胞的百分比。分别在瘤内和间质区室中分析了恶性细胞（程序性死亡配体1、B7 H3、B7 H4、吲哚胺2，3-双加氧酶1）和淋巴细胞（T细胞免疫球蛋白和含粘蛋白结构域3、T细胞活化的V结构域抑制因子、肿瘤坏死因子受体超家族成员4、淋巴细胞活化基因3、诱导型T细胞共刺激因子）上表达的检查点。在代表性亚组中，定量肿瘤内和肿瘤周围隔室中的免疫细胞密度。共有190例患者符合入选标准。Ki 67在鳞状细胞癌（平均31.4%阳性恶性细胞vs 15.2%腺癌，P<0.001）、晚期肿瘤（25.7% II/III期vs 20.8% I期，P = 0.013）和低分化肿瘤（28.8% vs 15.4%良好/中度，P <0.001）中的表达较高。Ki 67与肿瘤内程序性死亡配体1、B7-H3和吲哚胺2，3-双加氧酶1的表达以及淋巴细胞活化基因3和诱导性T细胞共刺激因子的基质表达升高呈正相关。Ki 67表达与肿瘤内CD 57+和CD 4+细胞密度呈负相关。Ki 67和检查点表达之间的关系在I期肿瘤中最强。在I期患者中，Ki 67升高与总生存率降低独立相关。Ki 67表达增加与生物侵袭性非小细胞肺癌、免疫检查点表达增强和肿瘤内免疫细胞浸润减少相关。这些发现在早期疾病中最强，需要在新型治疗药物的背景下进行进一步研究。
Ki67 is a marker for tumor proliferative activity and is known to have prognostic significance in multiple solid malignancies. We sought to characterize the relationships among Ki67 expression, immune cell infiltration, and immune checkpoint expression in patients with resected non–small cell lung cancer. Specimens of patients undergoing resection of stage I to III non–small cell lung cancer (1997–2012) were analyzed using tissue microarrays. Proliferative index was quantified as the percentage of malignant cells expressing Ki67. Checkpoints expressed on malignant cells (programmed death ligand 1, B7H3, B7H4, indoleamine 2,3-dioxygenase 1) and lymphocytes (T-cell immunoglobulin and mucin-domain containing 3, V-domain suppressor of T-cell activation, tumor necrosis factor receptor superfamily member 4, lymphocyte activation gene 3, inducible T-cell co-stimulator) were analyzed in intratumoral and stromal compartments, respectively. Immune cell densities were quantified in intratumoral and peritumoral compartments in a representative subset. A total of 190 patients met inclusion criteria. Higher Ki67 expression was noted in squamous cell carcinoma (median 31.4% positive malignant cells vs 15.2% adenocarcinoma, P<.001), advanced-stage tumors (25.7% stages II/III vs 20.8% stage I, P = .013), and poorly differentiated tumors (28.8% vs 15.4% well/moderately, P <.001). Ki67 was positively correlated with intratumoral expression of programmed death ligand 1, B7-H3, and indoleamine 2,3-dioxygenase 1, and elevated stromal expression of lymphocyte activation gene 3 and inducible T-cell co-stimulator. Ki67 expression was inversely associated with intratumoral densities of CD57+ and CD4+ cells. The relationship between Ki67 and checkpoint expression was strongest in stage I tumors. Among patients with stage I, increased Ki67 was independently associated with worse overall survival. Increased Ki67 expression is associated with biologically aggressive non–small cell lung cancer, enhanced immune checkpoint expression, and reduced intratumoral immune cell infiltration. These findings were strongest in early-stage disease and warrant further investigation in the context of novel therapeutic agents.
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影响因子：
5.8
作者：
Wei DM;Chen WJ;Meng RM;Zhao N;Zhang XY;Liao DY;Chen G
通讯作者：
Chen G
影响因子：
--
作者：
Soo RA;Chen Z;Yan Teng RS;Tan HL;Iacopetta B;Tai BC;Soong R
通讯作者：
Soong R
影响因子：
1.6
作者：
Sun X;Kaufman PD
通讯作者：
Kaufman PD
影响因子：
20.4
作者：
He, Yayi;Yu, Hui;Hirsch, Fred R.
通讯作者：
Hirsch, Fred R.
影响因子：
64.8
作者：
Cuylen S;Blaukopf C;Politi AZ;Müller-Reichert T;Neumann B;Poser I;Ellenberg J;Hyman AA;Gerlich DW
通讯作者：
Gerlich DW