PD-L1（CD274）拷贝数增加、表达及免疫细胞浸润作为软组织肉瘤对免疫检查点抑制剂反应的候选预测指标
PD-L1 (CD274) copy number gain, expression, and immune cell infiltration as candidate predictors for response to immune checkpoint inhibitors in soft-tissue sarcoma.
作者信息
Budczies Jan, Mechtersheimer Gunhild, Denkert Carsten, Klauschen Frederick, Mughal Sadaf S, Chudasama Priya, Bockmayr Michael, Jöhrens Korinna, Endris Volker, Lier Amelie, Lasitschka Felix, Penzel Roland, Dietel Manfred, Brors Benedikt, Gröschel Stefan, Glimm Hanno, Schirmacher Peter, Renner Marcus, Fröhling Stefan, Stenzinger Albrecht
机构信息
Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), partner sites Heidelberg and Berlin, and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Pathology, University Hospital Heidelberg , Heidelberg, Germany.
出版信息
Oncoimmunology. 2017 Jan 27;6(3):e1279777. doi: 10.1080/2162402X.2017.1279777. eCollection 2017.
Soft-tissue sarcomas (STS) are rare malignancies that account for 1% of adult cancers and comprise more than 50 entities. Current therapeutic options for advanced-stage STS are limited. Immune checkpoint inhibitors targeting the PD-1/PD-L1 signaling axis are being explored as new treatment modality in STS; however, the determinants of response to these agents are largely unknown. Using the sarcoma data set of The Cancer Genome Altas (TCGA) and an independent cohort of untreated high-grade STS, we analyzed DNA copy number status and mRNA expression of in a total of 335 STS cases. Copy number gains (CNG) were detected in 54 TCGA cases (21.1%), of which 21 (8.2%) harbored focal CNG and that were most prevalent in myxofibrosarcoma (35%) and undifferentiated pleomorphic sarcoma (34%). In the untreated high-grade STS cohort, we detected CNG in six cases (7.6%). Analysis of co-amplified genes identified a 5.6-Mb core region comprising 27 genes, including . Patients with CNG had higher expression compared with STS without CNG (fold change, 1.8; = 0.02), an effect that was most pronounced in the setting of focal CNG (fold change, 3.0; = 0.0027). STS with CNG showed a significantly higher mutational load compared with tumors with a diploid locus (median number of mutated genes; 58 vs. 40; = 3.6E-06), and CNG were associated with inferior survival (HR = 1.82; = 0.025). In contrast, T-cell infiltrates quantified by mRNA expression of were associated with improved survival (HR = 0.88; = 0.024) and consequently influenced the prognostic power of CNG, with low levels conferring poor survival in cases with CNG (HR = 1.8; = 0.049). These data demonstrate that GNG and elevated expression of occur in a substantial proportion of STS, have prognostic impact that is modulated by T-cell infiltrates, and thus warrant investigation as response predictors for immune checkpoint inhibition.
软组织肉瘤（STS）是罕见的恶性肿瘤，占成人癌症的1%，包含50多种类型。晚期STS的现有治疗选择有限。靶向PD-1/PD-L1信号轴的免疫检查点抑制剂正被探索作为STS的新治疗方式；然而，对这些药物反应的决定因素很大程度上尚不清楚。利用癌症基因组图谱（TCGA）的肉瘤数据集和一个未经治疗的高级别STS独立队列，我们分析了总共335例STS病例的DNA拷贝数状态和mRNA表达。在54例TCGA病例（21.1%）中检测到拷贝数增加（CNG），其中21例（8.2%）存在局灶性CNG，在黏液纤维肉瘤（35%）和未分化多形性肉瘤（34%）中最为常见。在未经治疗的高级别STS队列中，我们在6例（7.6%）中检测到CNG。对共扩增基因的分析确定了一个包含27个基因的5.6兆碱基核心区域，包括[具体基因名称未给出]。与无CNG的STS相比，有CNG的患者[相关基因名称未给出]表达更高（倍数变化，1.8；P = 0.02），在局灶性CNG情况下这种效应最为明显（倍数变化，3.0；P = 0.0027）。与二倍体[基因名称未给出]位点的肿瘤相比，有CNG的STS显示出显著更高的突变负荷（突变基因中位数；58对40；P = 3.6E - 06），且CNG与较差的生存率相关（HR = 1.82；P = 0.025）。相反，通过[相关基因名称未给出]mRNA表达量化的T细胞浸润与生存率提高相关（HR = 0.88；P = 0.024），因此影响了CNG的预后能力，在有CNG的病例中低[相关基因名称未给出]水平预示着较差的生存率（HR = 1.8；P = 0.049）。这些数据表明，[相关基因名称未给出]CNG和[相关基因名称未给出]表达升高在相当比例的STS中出现，具有受T细胞浸润调节预后的影响，因此作为免疫检查点抑制反应预测指标值得研究。
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