Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma.
Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma.
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DOI：
10.18632/oncotarget.6429
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发表时间：
2016-01-12
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影响因子：
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通讯作者：
Jöhrens K
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作者：
Darb-Esfahani S;Kunze CA;Kulbe H;Sehouli J;Wienert S;Lindner J;Budczies J;Bockmayr M;Dietel M;Denkert C;Braicu I;Jöhrens K
靶向检查点分子程序性细胞死亡1 （PD-1）及其配体PD-L1的抗体是新兴的癌症治疗方法。我们系统地研究了PD-1和PD-L1在预后不良肿瘤实体高级别浆液性卵巢癌中的表达模式。采用免疫组化技术，在215例原发性肿瘤细胞和肿瘤浸润淋巴细胞（TILs）的组织微阵列上检测PD-1和PD-L1蛋白的表达。采用定量反转录PCR法检测mRNA表达量。在癌症基因组图谱（TCGA）数据集中对mRNA数据进行了计算机验证。肿瘤细胞中PD-1和PD-L1表达、CD3+、PD-1+和PD-L1+ TILs密度以及PD-1和PD-L1 mRNA水平是无进展（PFS）和总生存（OS）的阳性预后因素，所有因素对PFS均显著（p < 0.035），对OS最显著。大多数因素也具有独立于年龄、分期和残余肿瘤的预后价值。此外，高PD-1+ TILs和PD-L1+ TILs密度增加了CD3+TILs的预后价值（PD-1+: p = 0.002, PD-L1+: p = 0.002）。PD-1和PD-L1 mRNA表达对预后的积极影响在TCGA基因表达数据集中可以重现（p = 0.02和p < 0.0001）。尽管PD-1和PD-L1具有免疫调节功能，但高水平的PD-1和PD-L1是卵巢癌预后良好的指标。我们的数据表明，PD-1和PD-L1分子是高级别浆液性卵巢癌免疫反应的生物学相关调节因子，这是评估免疫检查点抑制药物在这种肿瘤实体中的一个论据。
Antibodies targeting the checkpoint molecules programmed cell death 1 (PD-1) and its ligand PD-L1 are emerging cancer therapeutics. We systematically investigated PD-1 and PD-L1 expression patterns in the poor-prognosis tumor entity high-grade serous ovarian carcinoma. PD-1 and PD-L1 protein expression was determined by immunohistochemistry on tissue microarrays from 215 primary cancers both in cancer cells and in tumor-infiltrating lymphocytes (TILs). mRNA expression was measured by quantitative reverse transcription PCR. An in silico validation of mRNA data was performed in The Cancer Genome Atlas (TCGA) dataset. PD-1 and PD-L1 expression in cancer cells, CD3+, PD-1+, and PD-L1+ TILs densities as well as PD-1 and PD-L1 mRNA levels were positive prognostic factors for progression-free (PFS) and overall survival (OS), with all factors being significant for PFS (p < 0.035 each), and most being significant for OS. Most factors also had prognostic value that was independent from age, stage, and residual tumor. Moreover, high PD-1+ TILs as well as PD-L1+ TILs densities added prognostic value to CD3+TILs (PD-1+: p = 0.002,; PD-L1+: p = 0.002). The significant positive prognostic impact of PD-1 and PD-L1 mRNA expression could be reproduced in the TCGA gene expression datasets (p = 0.02 and p < 0.0001, respectively). Despite their reported immune-modulatory function, high PD-1 and PD-L1 levels are indicators of a favorable prognosis in ovarian cancer. Our data indicate that PD-1 and PD-L1 molecules are biologically relevant regulators of the immune response in high-grade serous ovarian carcinoma, which is an argument for the evaluation of immune checkpoint inhibiting drugs in this tumor entity.