FOXP3-based immune risk model for recurrence prediction in small-cell lung cancer at stages I-III.
FOXP3-based immune risk model for recurrence prediction in small-cell lung cancer at stages I-III.
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DOI：
10.1136/jitc-2021-002339
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发表时间：
2021-05
影响因子：
10.9
通讯作者：
Zhou C
中科院分区：
文献类型：
--
作者：
Jiang M;Wu C;Zhang L;Sun C;Wang H;Xu Y;Sun H;Zhu J;Zhao W;Fang Q;Yu J;Chen P;Wu S;Zheng Z;He Y;Zhou C
免疫疗法可以在一定程度上延长小细胞肺癌(SCLC)患者的生存时间。叉头盒蛋白P3(FOXP3)在肿瘤微环境(TME)中的作用仍存在争议。我们的目标是检测FOXP3相关的表达特征和预后价值，并开发临床相关的小细胞肺癌预测系统。我们招募了102例经组织学证实的I-III期小细胞肺癌患者。通过免疫组织化学方法，我们确定了FOXP3的表达模式及其与其他免疫生物标记物的相关性。通过机器学习和统计分析，构建了有效的免疫风险评分模型。此外，我们在不同的队列中研究了FOXP3相关的浓缩途径和TME特征。在小细胞肺癌中，FOXP3水平与程序性死亡配体1(PD-L1)、程序性细胞死亡蛋白1(PD-1)、CD_4、CD_8、CD_3显著相关(p=0.002，p=0.001，p=0.002，p=0.030，p<；0.001)。FOXP3高表达组无复发生存期(RFs)长于低表达组(41.200个月，95% CI为26.937~55.463，VS 14.000个月，95% CI为8.133~19.867；P=0.008)。对于肿瘤浸润性淋巴细胞(TIL)，亚群分析显示FOXP3和PD-1、PD-L1、淋巴细胞激活基因-3、CD3、CD4或CD8双阳性与较长的RFS显著相关。我们进一步进行了免疫生物标记物的重要性评估，构建了包含前三个重要生物标记物FOXP3、TIL PD-L1和CD8的免疫风险评分，并发现它们对预测小细胞肺癌复发具有独立的预后作用。与基于单一指标或基于两个指标的预测系统(曲线下面积0.715比0.312-0.711)相比，该免疫风险模型的预测性能更好。然后，建立了结合临床分期和免疫风险评分的复发预测系统，该系统在不同的队列中表现良好。FOXP3相关基因在多种免疫途径中均有丰富表达，其中白细胞介素2、CD28、碱性切除修复基因MUTYH、POLD1、POLD2、氧化磷酸化相关基因细胞色素c氧化酶8A与FOXP3表达密切相关。此外，我们发现低免疫风险评分组的活化的CD_4+记忆T细胞(p=0.014)和浆细胞(p=0.049)显著高于高风险组。肿瘤浸润性免疫细胞的异质性可能是小细胞肺癌风险预测的一个有前景的特征。Foxp3与TME中肿瘤浸润性细胞上的免疫生物标志物密切相互作用。这项研究强调了FOXP3在小细胞肺癌中的重要预后价值和临床应用前景。
Immunotherapies may prolong the survival of patients with small-cell lung cancer (SCLC) to some extent. The role of forkhead box protein P3 (FOXP3) in tumor microenvironment (TME) remains controversial. We aimed to examine FOXP3-related expression characteristics and prognostic values and to develop a clinically relevant predictive system for SCLC. We enrolled 102 patients with histologically confirmed SCLC at stages I–III. Through immunohistochemistry, we determined the expression pattern of FOXP3 and its association with other immune biomarkers. By machine learning and statistical analysis, we constructed effective immune risk score models. Furthermore, we examined FOXP3-related enrichment pathways and TME traits in distinct cohorts. In SCLC, FOXP3 level was significantly associated with status of programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), CD4, CD8, and CD3 (p=0.002, p=0.001, p=0.002, p=0.030, and p<0.001). High FOXP3 expression showed longer relapse-free survival (RFS) than the low-level group (41.200 months, 95% CI 26.937 to 55.463, vs 14.000 months, 95% CI 8.133 to 19.867; p=0.008). For tumor-infiltrating lymphocytes (TILs), subgroup analysis demonstrated FOXP3 and PD-1, PD-L1, lymphocyte activation gene-3, CD3, CD4, or CD8 double positive were significantly correlated with longer RFS. We further performed importance evaluation for immune biomarkers, constructed an immune risk score incorporating the top three important biomarkers, FOXP3, TIL PD-L1, and CD8, and found their independently prognostic role to predict SCLC relapse. Better predictive performance was achieved in this immune risk model compared with single-indicator-based or two-indicator-based prediction systems (area under the curve 0.715 vs 0.312–0.711). Then, relapse prediction system integrating clinical staging and immune risk score was established, which performed well in different cohorts. High FOXP3-related genes were enriched in several immune-related pathways, and the close relationships of interleukin-2, CD28, basic excision repair genes MUTYH, POLD1, POLD2, and oxidative phosphorylation related gene cytochrome c oxidase subunit 8A with FOXP3 expression were revealed. Moreover, we found low-immune risk score group had statistically higher activated CD4+ memory T cells (p=0.014) and plasma cells (p=0.049) than the high-risk group. The heterogeneity of tumor-infiltrating immune cells might represent a promising feature for risk prediction in SCLC. FOXP3 interacts closely with immune biomarkers on tumor-infiltrating cells in TME. This study highlighted the crucial prognostic value and promising clinical applications of FOXP3 in SCLC.
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影响因子：
11.2
作者：
Le Mercier I;Chen W;Lines JL;Day M;Li J;Sergent P;Noelle RJ;Wang L
通讯作者：
Wang L
DOI：
10.1097/cji.0b013e3181d32f01
发表时间：
2010-05
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Correale P;Rotundo MS;Del Vecchio MT;Remondo C;Migali C;Ginanneschi C;Tsang KY;Licchetta A;Mannucci S;Loiacono L;Tassone P;Francini G;Tagliaferri P
通讯作者：
Tagliaferri P
影响因子：
--
作者：
Syed Khaja AS;Toor SM;El Salhat H;Faour I;Ul Haq N;Ali BR;Elkord E
通讯作者：
Elkord E
影响因子：
20.4
作者：
He, Yayi;Yu, Hui;Hirsch, Fred R.
通讯作者：
Hirsch, Fred R.
影响因子：
20.4
作者：
Goldstraw, Peter;Chansky, Kari;Bolejack, Vanessa
通讯作者：
Bolejack, Vanessa