Chemoradiotherapy efficacy is predicted by intra-tumour CD8+/FoxP3+double positive T cell density in locally advanced N2 non-small-cell lung carcinoma
Chemoradiotherapy efficacy is predicted by intra-tumour CD8+/FoxP3+double positive T cell density in locally advanced N2 non-small-cell lung carcinoma
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DOI：
10.1016/j.ejca.2020.04.040
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发表时间：
2020-08-01
影响因子：
8.4
通讯作者：
Damotte, D.
中科院分区：
文献类型：
--
作者：
Boulle, G.;Velut, Y.;Damotte, D.
背景：放疗是局部晚期III期N2非小细胞肺癌（NSCLC）联合手术/化疗的标准治疗方法。放疗可诱导肿瘤免疫原性细胞死亡，释放新抗原，导致肿瘤内免疫浸润和体外效应。相反，尚未证明免疫细胞是否需要驱动放疗疗效和预测患者的生存。患者和方法：我们回顾性分析了113例患者的肿瘤样本和临床资料，其中89例切除（PORT）和24例未切除（DRC）的N2-NSCLC接受化疗和放疗（2002年至2015年同一放疗科）。免疫环境的特征是原位多重染色（CD8、FoxP3、PD-L1和细胞角蛋白），并与临床数据和生存率相关。结果：高CD8+ T细胞密度与PORT的OS （p = 0.04, HR = 1.93[0.99 -3.78]）和DFS （p = 0.003, HR = 2.42[1.31-4.47]）相关。CD8+/FoxP3+双阳性细胞密度高与整个人群的OS （p = 0.01, HR = 1.97[1.11 -3.48]）相关，PORT的OS （p = 0.05, HR = 1.92[0.98-3.74]）和PFS （p = 0.03, HR = 1.83[1.03-3.23]）相关，DRC无显著性差异。肿瘤细胞中PD-L1的中间表达（TPS = 1-49%）与PORT中较高的生存率相关。结论：肿瘤内CD8+ T细胞，特别是CD8+/FoxP3+双阳性T细胞密度预测III期N2-NSCLC的生存，提示需要预先存在的肿瘤内免疫来介导放疗的作用。在多变量分析中，CD8+/FoxP3+细胞密度是患者生存的最佳预测指标，可以作为放疗疗效的生物标志物。(C) 2020 Elsevier Ltd.版权所有。
Background: Radiotherapy is a standard of care for locally advanced stage III N2 non-small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival.Patients and methods: We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival.Results: High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99 -3.78]) and DFS (p = 0.003, HR = 2.42 [1.31-4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11 -3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98-3.74]) and PFS (p = 0.03, HR = 1.83 [1.03-3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1-49%) was associated with a higher survival in the PORT.Conclusions: Intra-tumoural CD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy. (C) 2020 Elsevier Ltd. All rights reserved.