Prognostic value of tumor-infiltrating lymphocytes (TILs) and their association with PD-L1 expression and DNA repair protein RAD51 in patients with resected non-small cell lung carcinoma
Prognostic value of tumor-infiltrating lymphocytes (TILs) and their association with PD-L1 expression and DNA repair protein RAD51 in patients with resected non-small cell lung carcinoma
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DOI：
10.1016/j.lungcan.2020.06.025
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发表时间：
2020-09-01
期刊：
影响因子：
5.3
通讯作者：
Joerger, Markus
中科院分区：
文献类型：
--
作者：
Gachechiladze, Mariam;Skarda, Josef;Joerger, Markus
目的：DNA修复蛋白已成为免疫治疗反应的潜在预测因子，与PD L1表达、肿瘤浸润淋巴细胞（TIL）和肿瘤突变负荷一起。我们分析了PD-L1的表达，TILs计数和同源重组（HR）蛋白RAD 51的表达，作为切除的非小细胞肺癌（NSCLC）患者的潜在预后因素。材料和方法：发现集包括96名NSCLC患者从大学医院奥洛穆茨（捷克共和国）和复制集包括1109名NSCLC患者从大学医院苏黎世（瑞士）。使用自动化染色平台Ventana Benchmark Ultra，用针对RAD 51、CD 3、CD 8、CD 68和PD-L1的抗体对组织微阵列（TMA）进行染色。核RAD 51蛋白的缺失与高TIL相关（r=-0.25，p = 0.01）和PD-L1状态（10.6 vs. 2.4%，p = 0.012）。来自TCGA数据集的计算机分析显示，RAD 51 mRNA表达与CD 45（r =-0.422，p < 0.0001）、CD 68（r =-0.326，p < 0.001）、CD 3（r =-0.266，p < 0.001）和CD 8（r =-0.102，p < 0.001）之间呈负相关。RAD 51低/PD-L1高患者在复制集和TCGA数据集中聚类为单独的实体。在复制组中，高TIL状态与OS改善显著相关（未校正HR = 0.57，95% CI 0.42-0.76，p < 0.001）。CD 3、CD 8和CD 68也有类似的结果。结论：在根治性切除的NSCLC患者中，术前接受新辅助化疗或放疗后，RAD 51核丢失与TIL增加和PD-L1升高呈弱相关。高TIL和RAD 51核丢失被证实是治愈性切除NSCLC的独立预后因素。
Objectives: DNA repair proteins have emerged as potential predictors for immunotherapy response alongside PD L1 expression, tumor-infiltrating lymphocytes (TILs) and tumor mutational burden. We analyzed expression of PD-L1, TILs count and expression of the homologous recombination (HR) protein RAD51, as potential prognostic factors in patients with resected non-small-cell lung carcinoma (NSCLC).Materials and methods: Discovery set included 96 NSCLC patients from the University Hospital Olomouc (Czech Republic) and a replication set included 1109 NSCLC patients from University Hospital Zurich (Switzerland). Tissue microarrays (TMAs) were stained using the automated staining platform Ventana Benchmark Ultra with antibodies against RAD51,CD3, CD8, CD68 and PD-L1.Results: Loss of nuclear RAD51 protein was associated with high TILs (r=-0.25, p = 0.01) and PD-L1 status (10.6 vs. 2.4 %, p = 0.012) in patients receiving neoadjuvant chemo-/radiotherapy (CT/RT). In silico analysis from the TCGA data set showed a negative relationship between RAD51 mRNA expression and CD45 (r =-0.422, p < 0.0001), CD68 (r =-0.326, p < 0.001), CD3 (r =-0.266, p < 0.001) and CD8 (r =-0.102, p < 0.001). RAD51 low/PD-L1 high patients were clustered as separate entity in the replication set and in TCGA dataset. High TILs status was significantly associated with improved OS in the replication set (unadjusted HR = 0.57, 95 % CI 0.42-0.76, p < 0.001). Similar results have been seen for CD3, CD8 and CD68.Conclusions: In conclusion, RAD51 nuclear loss is weakly associated with increased TILs and high PD-L1 at the time of surgery in curatively resected NSCLC and after prior exposure to neoadjuvant chemoor radiotherapy. Both high TILs and RAD51 nuclear loss were confirmed as independent prognostic factors in curatively resected NSCLC.