PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer
PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer
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在高级别浆液性卵巢癌中，程序性死亡配体1（PD-L1）的表达与肿瘤浸润性T细胞以及良好的预后相关。
DOI：
10.1016/j.ygyno.2016.03.008
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发表时间：
2016-05-01
影响因子：
4.7
通讯作者：
Nelson, Brad H.
中科院分区：
文献类型：
--
作者：
Webb, John R.;Milne, Katy;Nelson, Brad H.
目标。程序性死亡配体1 （Programmed Death Ligand 1, PD-L1）作为T细胞的负调节因子，既是抗肿瘤免疫反应的指示因子，也是抑制因子，其预后意义一直存在混淆。我们研究了上皮性卵巢癌中PD-L1表达的主要来源及其与肿瘤浸润淋巴细胞（TIL）和相关基因产物的关系。采用免疫组织化学方法评估来自最佳减体积患者的组织微阵列中含有高级别浆液性癌（HGSC）和子宫内膜样癌、透明细胞癌和粘液性卵巢癌的PD-L1和其他标志物（CD68、CD3、CD8、PD-1、CD103、FoxP3和CD25）的表达。通过癌症基因组图谱研究PD-L1表达与hgsc免疫相关转录和基因组特征之间的关系。PD-L1主要由肿瘤相关的CD68（+）巨噬细胞而不是肿瘤细胞表达。PD-L1（+）细胞经常与CD8、CD4和PD-1(+) TIL、CD25(+)FoxP3(+) treg和其他TIL亚群共定位。PD-L1（+）细胞在HGSC中预后有利。此外，PD-L1（+）细胞和CD8 TIL的存在比单独CD8 TIL的预后更好。PD-L1基因表达与BRCA状态无关。在转录水平上，PD-L1与细胞溶解（颗粒酶B、T-bet和ifn - γ）和抑制（PD-1、CTLA-4、LAG3和IDO-1）基因产物相关。PD-L1在卵巢癌中主要由巨噬细胞表达，并与细胞溶解和调节性TIL亚群密切相关，导致与生存呈正相关。含有PD-L1（+）巨噬细胞的肿瘤似乎陷入了免疫僵局，可能需要多管齐下的免疫治疗来缓解。爱思唯尔公司2016年版权所有版权所有。
Objective. As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti-tumor immune responses, which has led to confusion about its prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor infiltrating lymphocytes (TIL) and associated gene products.Methods. Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC.Results. PD-L1 was primarily expressed by tumor-associated CD68(+) macrophages rather than tumor cells. PD-L1(+) cells frequently co-localized with CD8, CD4 and PD-1(+) TIL, CD25(+)FoxP3(+) Tregs, and other TIL subsets. PD-L1(+) cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1(+) cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-gamma) and suppressive (PD-1, CTLA-4, LAG3 and IDO-1) gene products.Conclusions. PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1(+) macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate. Crown Copyright (C) 2016 Published by Elsevier Inc. All rights reserved.